Abuse-proofed dosage form
The present invention relates to an abuse-proofed, thermoformed dosage form containing, in addition to one or more active ingredients with abuse potential optionally together with physiologically acceptable auxiliary substances, at least one synthetic or natural polymer with a breaking strength of at least 500 N and to a process for the production thereof.
This application is a continuation of U.S. patent application Ser. No. 14/945,598, filed Nov. 19, 2015, which is a continuation of U.S. patent application Ser. No. 14/138,323, filed Dec. 23, 2013, now abandoned, which is a continuation of U.S. patent application Ser. No. 13/517,891, filed Jun. 14, 2012, now abandoned, which is, in turn, a divisional of U.S. patent application Ser. No. 13/346,257, filed Jan. 9, 2012, now U.S. Pat. No. 8,309,060, which is, in turn, a divisional of U.S. patent application Ser. No. 10/718,112, filed Nov. 20, 2003, now U.S. Pat. No. 8,114,383, which claims priority of German Application No. 103 36 400.5, filed Aug. 6, 2003.
The present invention relates to an abuse-proofed, thermoformed dosage form containing, in addition to one or more active ingredients with abuse potential (A) optionally together with physiologically acceptable auxiliary substances (B), at least one synthetic or natural polymer (C) and optionally at least one wax (D), wherein component (C) exhibits a breaking strength of at least 500 N, and to a process for the production of the dosage form according to the invention.
Many pharmaceutical active ingredients, in addition to having excellent activity in their appropriate application, also have abuse potential, i.e. they can be used by an abuser to bring about effects other than those intended. Opiates, for example, which are highly active in combating severe to very severe pain, are frequently used by abusers to induce a state of narcosis or euphoria.
In order to make abuse possible, the corresponding dosage forms, such as tablets or capsules are comminuted, for example ground in a mortar, by the abuser, the active ingredient is extracted from the resultant powder using a preferably aqueous liquid and the resultant solution, optionally after being filtered through cotton wool or cellulose wadding, is administered parenterally, in particular intravenously. An additional phenomenon of this kind of administration, in comparison with abusive oral administration, is a further accelerated increase in active ingredient levels giving the abuser the desired effect, namely the “kick” or “rush”. This kick is also obtained if the powdered dosage form is administered nasally, i.e. is sniffed. Since controlled-release dosage forms containing active ingredients with abuse potential do not give rise to the kick desired by the abuser when taken orally even in abusively high quantities, such dosage forms are also comminuted and extracted in order to be abused.
U.S. Pat. No. 4,070,494 proposed adding a swellable agent to the dosage form in order to prevent abuse. When water is added to extract the active ingredient, this agent swells and ensures that the filtrate separated from the gel contains only a small quantity of active ingredient.
The multilayer tablet disclosed in WO 95/20947 is based on a similar approach to preventing parenteral abuse, said tablet containing the active ingredient with abuse potential and at least one gel former, each in different layers.
WO 03/015531 A2 discloses another approach to preventing parenteral abuse. A dosage form containing an analgesic opioid and a dye as an aversive agent is described therein. The colour released by tampering with the dosage form is intended to discourage the abuser from using the dosage form which has been tampered with.
Another known option for complicating abuse involves adding antagonists to the active ingredients to the dosage form, for example naloxone or naltexone in the case of opiates, or compounds which cause a physiological defence response, such as for example Radix ipecacuanha=ipecac root.
However, since in most cases of abuse it is still necessary to pulverise the dosage form comprising an active ingredient suitable for abuse, it was the object of the present invention to complicate or prevent the pulverisation preceding abuse of the dosage form comprising the agents conventionally available for potential abuse and accordingly to provide a dosage form for active ingredients with abuse potential which ensures the desired therapeutic effect when correctly administered, but from which the active ingredients cannot be converted into a form suitable for abuse simply by pulverisation.
Said object has been achieved by the provision of the abuse-proofed, thermoformed dosage form according to the invention which contains, in addition to one or more active ingredients with abuse potential (A), at least one synthetic or natural polymer (C) and optionally at least one wax (D), wherein component (C) exhibits a breaking strength of at least 500 N.
The use of polymers having the stated minimum breaking strength, preferably in quantities such that the dosage form also exhibits such a minimum breaking strength, means that pulverisation of the dosage form is considerably more difficult using conventional means, so considerably complicating or preventing the subsequent abuse.
If comminution is inadequate, parenteral, in particular intravenous, administration cannot be performed safely or extraction of the active ingredient therefrom takes too long for the abuser or there is no “kick” when taken orally, as release is not spontaneous.
According to the invention, comminution is taken to mean pulverisation of the dosage form with conventional means which are available to an abuser, such as for example a mortar and pestle, a hammer, a mallet or other usual means for pulverisation by application of force.
The dosage form according to the invention is thus suitable for preventing parenteral, nasal and/or oral abuse of pharmaceutical active ingredients with abuse potential.
Pharmaceutical active ingredients with abuse potential are known to the person skilled in the art, as are the quantities thereof to be used and processes for the production thereof, and may be present in the dosage form according to the invention as such, in the form of the corresponding derivatives thereof, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof, as racemates or stereoisomers. The dosage form according to the invention is also suitable for the administration of several active ingredients. It is preferably used to administer a specific active ingredient.
The dosage form according to the invention is in particular suitable for preventing abuse of a pharmaceutical active ingredient selected from the group consisting of opiates, opioids, tranquillisers, preferably benzodiazepines, barbiturates, stimulants and other narcotics.
The dosage form according to the invention is very particularly suitable for preventing abuse of an opiate, opioid, tranquilliser or another narcotic selected from the group consisting of N-{1-[2-(4-ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-methoxymethyl-4-piperidyl}propionanilide (alfentanil), 5,5-diallylbarbituric acid (allobarbital), allylprodine, alphaprodine, 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine (alprazolam), 2-diethylaminopropiophenone (amfepramone), (±)-α-methylphenethylamine (amphetamine), 2-(α-methylphenethylamino)-2-phenylacetonitrile (amphetaminil), 5-ethyl-5-isopentylbarbituric acid (amobarbital), anileridine, apocodeine, 5,5-diethylbarbituric acid (barbital), benzylmorphine, bezitramide, 7-bromo-5-(2-pyridyl)-1H-1,4-benzodiazepine-2(3H)-one (bromazepam), 2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepine (brotizolam), 17-cyclopropylmethyl-4,5α-epoxy-7α[(S)-1-hydroxy-1,2,2-trimethyl-propyl]-6-methoxy-6,14-endo-ethanomorphinane-3-ol (buprenorphine), 5-butyl-5-ethylbarbituric acid (butobarbital), butorphanol, (7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepine-3-yl)-dimethylcarbamate (camazepam), (1S,2S)-2-amino-1-phenyl-1-propanol (cathine/D-norpseudoephedrine), 7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepine-2-ylamine-4-oxide (chlorodiazepoxide), 7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (clobazam), 5-(2-chlorophenyl)-7-nitro-1H-1,4-benzodiazepine-2(3H)-one (clonazepam), clonitazene, 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid (clorazepate), 5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-e][1,4]diazepine-2(3H)-one (clotiazepam), 10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepine-6(5H)-one (cloxazolam), (−)-methyl-[3β-benzoyloxy-2β(1αH,5αH)-tropancarboxylate] (cocaine), 4,5α-epoxy-3-methoxy-17-methyl-7-morphinene-6α-ol (codeine), 5-(1-cyclohexenyl)-5-ethylbarbituric acid (cyclobarbital), cyclorphan, cyprenorphine, 7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepine-2(3H)-one (delorazepam), desomorphine, dextromoramide, (+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate (dextropropoxyphen), dezocine, diampromide, diamorphone, 7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one (diazepam), 4,5α-epoxy-3-methoxy-17-methyl-6α-morphinanol (dihydrocodeine), 4,5α-epoxy-17-methyl-3,6a-morphinandiol (dihydromorphine), dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-1-ol (dronabinol), eptazocine, 8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (estazolam), ethoheptazine, ethylmethylthiambutene, ethyl [7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate] (ethyl loflazepate), 4,5α-epoxy-3-ethoxy-17-methyl-7-morphinene-6α-ol (ethylmorphine), etonitazene, 4,5α-epoxy-7α-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-al (etorphine), N-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine (fencamfamine), 7-[2-(α-methylphenethylamino)ethyl]-theophylline) (fenethylline), 3-(α-methylphenethylamino)propionitrile (fenproporex), N-(1-phenethyl-4-piperidyl)propionanilide (fentanyl), 7-chloro-5-(2-fluorophenyl)-1-methyl-1H-1,4-benzodiazepine-2(3H)-one (fludiazepam), 5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepine-2(3H)-one (flunitrazepam), 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepine-2(3H)-one (flurazepam), 7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepine-2(3H)-one (halazepam), 10-bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]oxazolyl[3,2-d][1,4]benzodiazepine-6(5H)-one (haloxazolam), heroin, 4,5α-epoxy-3-methoxy-17-methyl-6-morphinanone (hydrocodone), 4,5α-epoxy-3-hydroxy-17-methyl-6-morphinanone (hydromorphone), hydroxypethidine, isomethadone, hydroxymethyl morphinane, 11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]oxazino[3,2-d][1,4]benzodiazepine-4,7(6H)-dione (ketazolam), 1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone (ketobemidone), (3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-yl acetate (levacetylmethadol (LAAM)), (−)-6-dimethylamino-4,4-diphenol-3-heptanone (levomethadone), (−)-17-methyl-3-morphinanol (levorphanol), levophenacylmorphane, lofentanil, 6-(2-chlorophenyl)-2-(4-methyl-1-piperazinylmethylene)-8-nitro-2H-imidazo[1,2-a][1,4]-benzodiazepine-1(4H)-one (loprazolam), 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepine-2(3H)-one (lorazepam), 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1H-1,4-benzodiazepine-2(3H)-one (lormetazepam), 5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol (mazindol), 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine (medazepam), N-(3-chloropropyl)-α-methylphenethylamine (mefenorex), meperidine, 2-methyl-2-propyltrimethylene dicarbamate (meprobamate), meptazinol, metazocine, methylmorphine, N,α-dimethylphenethylamine (methamphetamine), (±)-6-dimethylamino-4,4-diphenyl-3-heptanone (methadone), 2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone), methyl [2-phenyl-2-(2-piperidyl)acetate] (methylphenidate), 5-ethyl-1-methyl-5-phenylbarbituric acid (methylphenobarbital), 3,3-diethyl-5-methyl-2,4-piperidinedione (methyprylon), metopon, 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam), 2-(benzhydrylsulfinyl)-acetamide (modafinil), 4,5α-epoxy-17-methyl-7-morphines-3,6α-diol (morphine), myrophine, (±)-trans-3-(1,1-dimethylheptyl)-7,8,10,10α-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyrane-9(6αH)-one (nabilone), nalbuphine, nalorphine, narceine, nicomorphine, 1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one (nimetazepam), 7-nitro-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one (nitrazepam), 7-chloro-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one (nordazepam), norlevorphanol, 6-dimethylamino-4,4-diphenyl-3-hexanone (normethadone), normorphine, norpipanone, the exudation of plants belonging to the species Papaver somniferum (opium), 7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one (oxazepam), (cis-trans)-10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepine-6-(5H)-one (oxazolam), 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone (oxycodone), oxymorphone, plants and parts of plants belonging to the species Papaver somniferum (including the subspecies setigerum), papaveretum, 2-imino-5-phenyl-4-oxazolidinone (pernoline), 1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol (pentazocine), 5-ethyl-5-(1-methylbutyl)-barbituric acid (pentobarbital), ethyl-(1-methyl-4-phenyl-4-piperidine carboxylate) (pethidine), phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, pholcodine, 3-methyl-2-phenylmorpholine (phenmetrazine), 5-ethyl-5-phenylbarbituric acid (phenobarbital), α,α-dimethylphenethylamine (phentermine), 7-chloro-5-phenyl-1-(2-propynyl)-1H-1,4-benzodiazepine-2(3H)-one (pinazepam), α-(2-piperidyl)benzhydryl alcohol (pipradrol), 1′-(3-cyano-3,3-diphenylpropyl)[1,4′-bipiperidine]-4′-carboxamide (piritramide), 7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one (prazepam), profadol, proheptazine, promedol, properidine, propoxyphene, N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, methyl {3-[4-methoxycarbonyl-4-(N-phenylpropanamido)piperidino]propanoate} (remifentanil), 5-sec-butyl-5-ethylbarbituric acid (secbutabarbital), 5-allyl-5-(1-methylbutyl)-barbituric acid (secobarbital), N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}-propionanilide (sufentanil), 7-chloro-2-hydroxy-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (temazepam), 7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepine-2(3H)-one (tetrazepam), ethyl (2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate) (tilidine (cis and trans)), tramadol, 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (triazolam), 5-(1-methylbutyl)-5-vinylbarbituric acid (vinylbital), (1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol, (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol, (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol, (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl 2-(4-isobutoxy-phenyl)-propionate, 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl 2-(6-methoxy-naphthalen-2-yl)-propionate, 3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-(4-isobutyl-phenyl)-propionate, 3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-(6-methoxy-naphthalen-2-yl)-propionate, (RR—SS)-2-acetoxy-4-trifluoromethyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR—SS)-2-hydroxy-4-trifluoromethyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR—SS)-4-chloro-2-hydroxy-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR—SS)-2-hydroxy-4-methyl-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR—SS)-2-hydroxy-4-methoxy-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR—SS)-2-hydroxy-5-nitro-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR—SS)-2′,4′-difluoro-3-hydroxy-biphenyl-4-carboxylic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester and for corresponding stereoisomeric compounds, the corresponding derivatives thereof in each case, in particular esters or ethers, and the physiologically acceptable compounds thereof in each case, in particular the salts and solvates thereof.
The compounds (1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol or the stereoisomeric compounds thereof or the physiologically acceptable compounds thereof, in particular the hydrochlorides thereof, the derivatives thereof, such as esters or ethers, and processes for the production thereof are known, for example, from EP-A-693475 or EP-A-780369. The corresponding descriptions are hereby introduced as a reference and are deemed to be part of the disclosure.
In order to achieve the necessary breaking strength of the dosage form according to the invention, at least one synthetic or natural polymer (C) is used which has a breaking strength, measured using the method disclosed in the present application, of at least 500 N. At least one polymer selected from the group consisting of polymethylene oxide, polyethylene oxide, polypropylene oxide, polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, copolymers thereof, and mixtures of at least two of the stated polymers is preferably used for this purpose. The polymers are distinguished by a molecular weight of at least 0.5 million, determined by rheological measurements. Thermoplastic polyalkylene oxides, such as polyethylene oxides, with a molecular weight of at least 0.5 million, preferably of up to 15 million, determined by rheological measurements, are very particularly preferred. These polymers have a viscosity at 25° C. of 4500 to 17600 cP, measured on a 5 wt. % aqueous solution using a model RVF Brookfield viscosimeter (spindle no. 2/rotational speed 2 rpm), of 400 to 4000 cP, measured on a 2 wt. % aqueous solution using the stated viscosimeter (spindle no. 1 or 3/rotational speed 10 rpm) or of 1650 to 10000 cP, measured on a 1 wt. % aqueous solution using the stated viscosimeter (spindle no. 2/rotational speed 2 rpm).
In an embodiment, the component (C) is used in at least 60 wt %.
The polymers are used in powder form.
In order to achieve the necessary breaking strength of the dosage form according to the invention, it is furthermore possible additionally to use at least one natural or synthetic wax (D) with a breaking strength, measured using the method disclosed in the present application, of at least 500 N. Waxes with a softening point of at least 60° C. are preferred. Carnauba wax and beeswax are particularly preferred. Carnauba wax is very particularly preferred. Carnauba wax is a natural wax which is obtained from the leaves of the carnauba palm and has a softening point of 80° C. When the wax component is additionally used, it is used together with at least one polymer (C) in quantities such that the dosage form has a breaking strength of at least 500 N.
The dosage forms according to the invention are distinguished in that, due their hardness, they cannot be pulverised, for example by grinding in a mortar. This virtually rules out oral or parenteral, in particular intravenous or nasal abuse. However, in order to prevent any possible abuse in the event of comminution and/or pulverisation of the dosage form according to the invention which has nevertheless been achieved by application of extreme force, the dosage forms according to the invention may, in a preferred embodiment, contain further agents which complicate or prevent abuse as auxiliary substances (B).
The abuse-proofed dosage form according to the invention, which comprises, apart from one or more active ingredients with abuse potential, at least one hardening polymer (C) and optionally at least one wax (D), may accordingly also comprise at least one of the following components (a)-(f) as auxiliary substances (B):
-
- (a) at least one substance which irritates the nasal passages and/or pharynx,
- (b) at least one viscosity-increasing agent, which, with the assistance of a necessary minimum quantity of an aqueous liquid, forms a gel with the extract obtained from the dosage form, which gel preferably remains visually distinguishable when introduced into a further quantity of an aqueous liquid,
- (c) at least one antagonist for each of the active ingredients with abuse potential,
- (d) at least one emetic,
- (e) at least one dye as an aversive agent,
- (f) at least one bitter substance.
Components (a) to (f) are additionally each individually suitable for abuse-proofing the dosage form according to the invention. Accordingly, component (a) is preferably suitable for proofing the dosage form against nasal, oral and/or parenteral, preferably intravenous, abuse, component (b) is preferably suitable for proofing against parenteral, particularly preferably intravenous and/or nasal abuse, component (c) is preferably suitable for proofing against nasal and/or parenteral, particularly preferably intravenous, abuse, component (d) is preferably suitable for proofing against parenteral, particularly preferably intravenous, and/or oral and/or nasal abuse, component (e) is suitable as a visual deterrent against oral or parenteral abuse and component (f) is suitable for proofing against oral or nasal abuse. Combined use according to the invention of at least one of the above-stated components makes it possible still more effectively to prevent abuse of dosage forms according to the invention.
In one embodiment, the dosage form according to the invention may also comprise two or more of components (a)-(f) in a combination, preferably (a), (b) and optionally (c) and/or (f) and/or (e) or (a), (b) and optionally (d) and/or (f) and/or (e).
In another embodiment, the dosage form according to the invention may comprise all of components (a)-(f).
If the dosage form according to the invention comprises component (a) to counter abuse, substances which irritate the nasal passages and/or pharynx which may be considered according to the invention are any substances which, when administered via the nasal passages and/or pharynx, bring about a physical reaction which is either so unpleasant for the abuser that he/she does not wish to or cannot continue administration, for example burning, or physiologically counteracts taking of the corresponding active ingredient, for example due to increased nasal secretion or sneezing. These substances which conventionally irritate the nasal passages and/or pharynx may also bring about a very unpleasant sensation or even unbearable pain when administered parenterally, in particular intravenously, such that the abuser does not wish to or cannot continue taking the substance.
Particularly suitable substances which irritate the nasal passages and/or pharynx are those which cause burning, itching, an urge to sneeze, increased formation of secretions or a combination of at least two of these stimuli. Appropriate substances and the quantities thereof which are conventionally to be used are known per se to the skilled person or may be identified by simple preliminary testing.
The substance which irritates the nasal passages and/or pharynx of component (a) is preferably based on one or more constituents or one or more plant parts of at least one hot substance drug.
Corresponding hot substance drugs are known per se to the person skilled in the art and are described, for example, in “Pharmazeutische Biologie—Drogen and ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner, 2nd., revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982, pages 82 et seq. The corresponding description is hereby introduced as a reference and is deemed to be part of the disclosure.
The dosage form according to the invention may preferably contain the plant parts of the corresponding hot substance drugs in a quantity of 0.01 to 30 wt. %, particularly preferably of 0.1 to 0.5 wt. %, in each case relative to the total weight dosage unit.
If one or more constituents of corresponding hot substance drugs are used, the quantity thereof in a dosage unit according to the invention preferably amounts to 0.001 to 0.005 wt. %, relative to the total weight of the dosage unit.
A dosage unit is taken to mean a separate or separable administration unit, such as for example a tablet or a capsule.
One or more constituents of at least one hot substance drug selected from the group consisting of Allii sativi bulbus (garlic), Asari rhizoma cum herba (Asarum root and leaves), Calami rhizoma (calamus root), Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper), Curcumae longae rhizoma (turmeric root), Curcumae xanthorrhizae rhizoma (Javanese turmeric root), Galangae rhizoma (galangal root), Myristicae semen (nutmeg), Piperis nigri fructus (pepper), Sinapis albae semen (white mustard seed), Sinapis nigri semen (black mustard seed), Zedoariae rhizoma (zedoary root) and Zingiberis rhizoma (ginger root), particularly preferably from the group consisting of Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper) and Piperis nigri fructus (pepper) may preferably be added as component (a) to the dosage form according to the invention.
The constituents of the hot substance drugs preferably comprise o-methoxy(methyl)phenol compounds, acid amide compounds, mustard oils or sulfide compounds or compounds derived therefrom.
Particularly preferably, at least one constituent of the hot substance drugs is selected from the group consisting of myristicin, elemicin, isoeugenol, β-asarone, safrole, gingerols, xanthorrhizol, capsaicinoids, preferably capsaicin, capsaicin derivatives, such as N-vanillyl-9E-octadecenamide, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, norcapsaicin and nomorcapsaicin, piperine, preferably trans-piperine, glucosinolates, preferably based on non-volatile mustard oils, particularly preferably based on p-hydroxybenzyl mustard oil, methylmercapto mustard oil or methylsulfonyl mustard oil, and compounds derived from these constituents.
Another option for preventing abuse of the dosage form according to the invention consists in adding at least one viscosity-increasing agent as a further abuse-preventing component (b) to the dosage form, which, with the assistance of a necessary minimum quantity of an aqueous liquid, forms a gel with the extract obtained from the dosage form, which gel is virtually impossible to administer safely and preferably remains visually distinguishable when introduced into a further quantity of an aqueous liquid.
For the purposes of the present invention visually distinguishable means that the active ingredient-containing gel formed with the assistance of a necessary minimum quantity of aqueous liquid, when introduced, preferably with the assistance of a hypodermic needle, into a further quantity of aqueous liquid at 37° C., remains substantially insoluble and cohesive and cannot straightforwardly be dispersed in such a manner that it can safely be administered parenterally, in particular intravenously. The material preferably remains visually distinguishable for at least one minute, preferably for at least 10 minutes.
The increased viscosity of the extract makes it more difficult or even impossible for it to be passed through a needle or injected. If the gel remains visually distinguishable, this means that the gel obtained on introduction into a further quantity of aqueous liquid, for example by injection into blood, initially remains in the form of a largely cohesive thread, which, while it may indeed be broken up into smaller fragments, cannot be dispersed or even dissolved in such a manner that it can safely be administered parenterally, in particular intravenously. In combination with at least one optionally present component (a) to (e), this additionally leads to unpleasant burning, vomiting, bad flavour and/or visual deterrence.
Intravenous administration of such a gel would most probably result in obstruction of blood vessels, associated with serious embolism or even death of the abuser.
In order to verify whether a viscosity-increasing agent is suitable as component (b) for use in the dosage form according to the invention, the active ingredient is mixed with the viscosity-increasing agent and suspended in 10 ml of water at a temperature of 25° C. If this results in the formation of a gel which fulfils the above-stated conditions, the corresponding viscosity-increasing agent is suitable for preventing or averting abuse of the dosage forms according to the invention.
If component (b) is added to the dosage form according to the invention, one or more viscosity-increasing agents are used which are selected from the group consisting of microcrystalline cellulose with 11 wt. % carboxymethylcellulose sodium (Avicel® RC 591), carboxymethylcellulose sodium (Blanose®, CMC-Na C300P®, Frimulsion BLC-5®, Tylose C300 PC)), polyacrylic acid (Carbopol® 980 NF, Carbopol® 981), locust bean flour (Cesagum® LA-200, Cesagum® LID/150, Cesagum® LN-1), pectins such as citrus pectin (Cesapectin® HM Medium Rapid Set), apple pectin, pectin from lemon peel, waxy maize starch (C*Gel 04201®), sodium alginate (Frimulsion ALG (E401)®), guar flour (Frimulsion BM®, Polygum 26/1-75®), iota carrageen (Frimulsion D021®), karaya gum, gellan gum (Kelcogel F®, Kelcogel LT100®), galactomannan (Meyprogat 150®), tara bean flour (Polygum 43/1®), propylene glycol alginate (Protanal-Ester SD-LB®)), sodium hyaluronate, tragacanth, tara gum (Vidogum SP 200®), fermented polysaccharide welan gum (K1A96), xanthan gum (Xantural 180®). Xanthans are particularly preferred. The names stated in brackets are the trade names by which the materials are known commercially. In general, a quantity of 0.1 to 5 wt. % of the viscosity-increasing agent(s) is sufficient to fulfil the above-stated conditions.
The component (b) viscosity-increasing agents, where provided, are preferably present in the dosage form according to the invention in quantities of ≥5 mg per dosage unit, i.e. per administration unit.
In a particularly preferred embodiment of the present invention, the viscosity-increasing agents used as component (b) are those which, on extraction from the dosage form with the necessary minimum quantity of aqueous liquid, form a gel which encloses air bubbles. The resultant gels are distinguished by a turbid appearance, which provides the potential abuser with an additional optical warning and discourages him/her from administering the gel parenterally.
It is also possible to formulate the viscosity-increasing agent and the other constituents in the dosage form according to the invention in a mutually spatially separated arrangement.
In order to discourage and prevent abuse, the dosage form according to the invention may furthermore comprise component (c), namely one or more antagonists for the active ingredient or active ingredients with abuse potential, wherein the antagonists are preferably spatially separated from the remaining constituents of the invention dosage according to the form and, when correctly used, do not exert any effect.
Suitable antagonists for preventing abuse of the active ingredients are known per se to the person skilled in the art and may be present in the dosage form according to the invention as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof.
If the active ingredient present in the dosage form is an opiate or an opioid, the antagonist used is preferably an antagonist selected from the group consisting of naloxone, naltrexone, nalmefene, nalid, nalmexone, nalorphine or naluphine, in each case optionally in the form of a corresponding physiologically acceptable compound, in particular in the form of a base, a salt or solvate. The corresponding antagonists, where component (c) is provided, are preferably used in a quantity of ≥10 mg, particularly preferably in a quantity of 10 to 100 mg, very particularly preferably in a quantity of 10 to 50 mg per dosage form, i.e. per administration unit.
If the dosage form according to the invention comprises a stimulant as active ingredient, the antagonist is preferably a neuroleptic, preferably at least one compound selected from the group consisting of haloperidol, promethazine, fluphenazine, perphenazine, levomepromazine, thioridazine, perazine, chlorpromazine, chlorprothixine, zuclopentixol, flupentixol, prothipendyl, zotepine, benperidol, pipamperone, melperone and bromperidol.
The dosage form according to the invention preferably comprises these antagonists in a conventional therapeutic dose known to the person skilled in the art, particularly preferably in a quantity of twice to four times the conventional dose per administration unit.
If the combination to discourage and prevent abuse of the dosage form according to the invention comprises component (d), it may comprise at least one emetic, which is preferably present in a spatially separated arrangement from the other components of the dosage form according to the invention and, when correctly used, is intended not to exert its effect in the body.
Suitable emetics for preventing abuse of an active ingredient are known per se to the person skilled in the art and may be present in the dosage form according to the invention as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of the salts or solvates thereof.
An emetic based on one or more constituents of radix ipecacuanha (ipecac root), preferably based on the constituent emetine may preferably be considered in the dosage form according to the invention, as are, for example, described in “Pharmazeutische Biologie—Drogen and ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag, Stuttgart, N.Y., 1982. The corresponding literature description is hereby introduced as a reference and is deemed to be part of the disclosure.
The dosage form according to the invention may preferably comprise the emetic emetine as component (d), preferably in a quantity of ≥10 mg, particularly preferably of ≥20 mg and very particularly preferably in a quantity of ≥40 mg per dosage form, i.e. administration unit.
Apomorphine may likewise preferably be used as an emetic in the abuse-proofing according to the invention, preferably in a quantity of preferably ≥3 mg, particularly preferably of ≥5 mg and very particularly preferably of ≥7 mg per administration unit.
If the dosage form according to the invention contains component (e) as a further abuse-preventing auxiliary substance, the use of a such a dye brings about an intense coloration of a corresponding aqueous solution, in particular when the attempt is made to extract the active ingredient for parenteral, preferably intravenous administration, which coloration may act as a deterrent to the potential abuser. Oral abuse, which conventionally begins by means of aqueous extraction of the active ingredient, may also be prevented by this coloration. Suitable dyes and the quantities required for the necessary deterrence may be found in WO 03/015531, wherein the corresponding disclosure should be deemed to be part of the present disclosure and is hereby introduced as a reference.
If the dosage form according to the invention contains component (f) as a further abuse-preventing auxiliary substance, this addition of at least one bitter substance and the consequent impairment of the flavour of the dosage form additionally prevents oral and/or nasal abuse.
Suitable bitter substances and the quantities effective for use may be found in US-2003/0064099 A1, the corresponding disclosure of which should be deemed to be the disclosure of the present application and is hereby introduced as a reference. Suitable bitter substances are preferably aromatic oils, preferably peppermint oil, eucalyptus oil, bitter almond oil, menthol, fruit aroma substances, preferably aroma substances from lemons, oranges, limes, grapefruit or mixtures thereof, and/or denatonium benzoate.
The solid dosage form according to the invention is suitable to be taken orally or rectally, preferably orally. The orally administrable dosage form according to the invention may assume multiparticulate form, preferably in the form of microtablets, microcapsules, micropellets, granules, spheroids, beads or pellets, optionally packaged in capsules or pressed into tablets. The multiparticulate forms preferably have a size or size distribution in the range from 0.1 to 3 mm, particularly preferably in the range from 0.5 to 2 mm. Depending on the desired dosage form, conventional auxiliary substances (B) are optionally also used for the formulation of the dosage form.
The solid, abuse-proofed dosage form according to the invention is preferably produced by mixing the components (A), (B), (C) and/optionally (D) and at least one of the optionally present further abuse-preventing components (a)-(f) and, optionally after granulation, press-forming the resultant mixture to yield the dosage form with preceding, simultaneous, or subsequent exposure to heat.
Mixing of components (A), (B), (C) and optionally (D) and of the optionally present further components (a)-(f) proceeds in a mixer known to the person skilled in the art. The mixer may, for example, be a roll mixer, shaking mixer, shear mixer or compulsory mixer.
The resultant mixture is preferably formed directly by application of pressure to yield the dosage form according to the invention with preceding, simultaneous or subsequent exposure to heat. The mixture may, for example, be formed into tablets by direct tabletting. In direct tabletting with simultaneous exposure to heat, the tabletting tool, i.e. bottom punch, top punch and die are briefly heated at least to the softening temperature of the polymer (C) and pressed together. In direct tabletting with subsequent exposure to heat, the formed tablets are briefly heated at least to the softening temperature (glass transition temperature, melting temperature; sintering temperature) of component (C) and cooled again. In direct tabletting with preceding exposure to heat, the material to be pressed is heated immediately prior to tabletting at least to the softening temperature of component (C) and then pressed.
The resultant mixture of components (A), (B), (C) and optionally (D) and the optionally present components (a) to (f) may also first be granulated and then be formed with preceding, simultaneous, or subsequent exposure to heat to yield the dosage form according to the invention.
In a further preferred embodiment, the dosage form according to the invention assumes the form of a tablet, a capsule or is in the form of an oral osmotic therapeutic system (OROS), preferably if at least one further abuse-preventing component (a)-(f) is also present.
If components (c) and/or (d) and/or (f) are present in the dosage form according to the invention, care must be taken to ensure that they are formulated in such a manner or are present in such a low dose that, when correctly administered, the dosage form is able to bring about virtually no effect which impairs the patient or the efficacy of the active ingredient.
If the dosage form according to the invention contains component (d) and/or (f), the dosage must be selected such that, when correctly orally administered, no negative effect is caused. If, however, the intended dosage of the dosage form is exceeded inadvertently, in particular by children, or in the event of abuse, nausea or an inclination to vomit or a bad flavour are produced. The particular quantity of component (d) and/or (f) which can still be tolerated by the patient in the event of correct oral administration may be determined by the person skilled in the art by simple preliminary testing.
If, however, irrespective of the fact that the dosage form according to the invention is virtually impossible to pulverise, the dosage form containing the components (c) and/or (d) and/or (f) is provided with protection, these components should preferably be used at a dosage which is sufficiently high that, when abusively administered, they bring about an intense negative effect on the abuser. This is preferably achieved by spatial separation of at least the active ingredient or active ingredients from components (c) and/or (d) and/or (f), wherein the active ingredient or active ingredients is/are present in at least one subunit (X) and components (c) and/or (d) and/or (f) is/are present in at least one subunit (Y), and wherein, when the dosage form is correctly administered, components (c), (d) and (f) do not exert their effect on taking and/or in the body and the remaining components of the formulation, in particular component (C), are identical.
If the dosage form according to the invention comprises at least 2 of components (c) and (d) or (f), these may each be present in the same or different subunits (Y). Preferably, when present, all the components (c) and (d) and (f) are present in one and the same subunit (Y).
For the purposes of the present invention, subunits are solid formulations, which in each case, apart from conventional auxiliary substances known to the person skilled in the art, contain the active ingredient(s), at least one polymer (C) and optionally at least one of the optionally present components (a) and/or (b) and/or (e) or in each case at least one polymer (C) and the antagonist(s) and/or emetic(s) and/or component (e) and/or component (f) and optionally at least one of the optionally present components (a) and/or (b). Care must here be taken to ensure that each of the subunits is formulated in accordance with the above-stated process.
One substantial advantage of the separated formulation of active ingredients from components (c) or (d) or (f) in subunits (X) and (Y) of the dosage form according to the invention is that, when correctly administered, components (c) and/or (d) and/or (f) are hardly released on taking and/or in the body or are released in such small quantities that they exert no effect which impairs the patient or therapeutic success or, on passing through the patient's body, they are only liberated in locations where they cannot be sufficiently absorbed to be effective. When the dosage form is correctly administered, hardly any of components (c) and/or (d) and/or (f) is released into the patient's body or they go unnoticed by the patient.
The person skilled in the art will understand that the above-stated conditions may vary as a function of the particular components (c), (d) and/or (f) used and of the formulation of the subunits or the dosage form. The optimum formulation for the particular dosage form may be determined by simple preliminary testing. What is vital is that each subunit contains the polymer (C) and has been formulated in the stated manner.
Should, contrary to expectations, the abuser succeed in comminuting such a dosage form according to the invention, which comprises components (c) and/or (e) and/or (d) and/or (f) in subunits (Y), for the purpose of abusing the active ingredient and obtain a powder which is extracted with a suitable extracting agent, not only the active ingredient but also the particular component (c) and/or (e) and/or (f) and/or (d) will be obtained in a form in which it cannot readily be separated from the active ingredient, such that when the dosage form which has been tampered with is administered, in particular by oral and/or parenteral administration, it will exert its effect on taking and/or in the body combined with an additional negative effect on the abuser corresponding to component (c) and/or (d) and/or (f) or, when the attempt is made to extract the active ingredient, the coloration will act as a deterrent and so prevent abuse of the dosage form.
A dosage form according to the invention, in which the active ingredient or active ingredients is/are spatially separated from components (c), (d) and/or (e), preferably by formulation in different subunits, may be formulated in many different ways, wherein the corresponding subunits may each be present in the dosage form according to the invention in any desired spatial arrangement relative to one another, provided that the above-stated conditions for the release of components (c) and/or (d) are fulfilled.
The person skilled in the art will understand that component(s) (a) and/or (b) which are optionally also present may preferably be formulated in the dosage form according to the invention both in the particular subunits (X) and (Y) and in the form of independent subunits corresponding to subunits (X) and (Y), provided that neither the abuse-proofing nor the active ingredient release in the event of correct administration is impaired by the nature of the formulation and the polymer (C) is included in the formulation and formulation is carried out in accordance with the above-stated process.
In a preferred embodiment of the dosage form according to the invention, subunits (X) and (Y) are present in multiparticulate form, wherein microtablets, microcapsules, micropellets, granules, spheroids, beads or pellets are preferred and the same form, i.e. shape, is selected for both subunit (X) and subunit (Y), such that it is not possible to separate subunits (X) from (Y) by mechanical selection. The multiparticulate forms are preferably of a size in the range from 0.1 to 3 mm, preferably of 0.5 to 2 mm.
The subunits (X) and (Y) in multiparticulate form may also preferably be packaged in a capsule or be pressed into a tablet, wherein the final formulation in each case proceeds in such a manner that the subunits (X) and (Y) are also retained in the resultant dosage form.
The multiparticulate subunits (X) and (Y) of identical shape should also not be visually distinguishable from one another so that the abuser cannot separate them from one another by simple sorting. This may, for example, be achieved by the application of identical coatings which, apart from this disguising function, may also incorporate further functions, such as, for example, controlled release of one or more active ingredients or provision of a finish resistant to gastric juices on the particular subunits.
In a further preferred embodiment of the present invention, subunits (X) and (Y) are in each case arranged in layers relative to one another.
The layered subunits (X) and (Y) are preferably arranged for this purpose vertically or horizontally relative to one another in the dosage form according to the invention, wherein in each case one or more layered subunits (X) and one or more layered subunits (Y) may be present in the dosage form, such that, apart from the preferred layer sequences (X)-(Y) or (X)-(Y)-(X), any desired other layer sequences may be considered, optionally in combination with layers containing components (a) and/or (b).
Another preferred dosage form according to the invention is one in which subunit (Y) forms a core which is completely enclosed by subunit (X), wherein a separation layer (Z) may be present between said layers. Such a structure is preferably also suitable for the above-stated multiparticulate forms, wherein both subunits (X) and (Y) and an optionally present separation layer (Z), which must satisfy the hardness requirement according to the invention, are formulated in one and the same multiparticulate form. In a further preferred embodiment of the dosage form according to the invention, the subunit (X) forms a core, which is enclosed by subunit (Y), wherein the latter comprises at least one channel which leads from the core to the surface of the dosage form.
The dosage form according to the invention may comprise, between one layer of the subunit (X) and one layer of the subunit (Y), in each case one or more, preferably one, optionally swellable separation layer (Z) which serves to separate subunit (X) spatially from (Y).
If the dosage form according to the invention comprises the layered subunits (X) and (Y) and an optionally present separation layer (Z) in an at least partially vertical or horizontal arrangement, the dosage form preferably takes the form of a tablet, a coextrudate or a laminate.
In one particularly preferred embodiment, the entirety of the free surface of subunit (Y) and optionally at least part of the free surface of subunit(s) (X) and optionally at least part of the free surface of the optionally present separation layer(s) (Z) may be coated with at least one barrier layer (Z′) which prevents release of component (c) and/or (e) and/or (d) and/or (f). The barrier layer (Z′) must also fulfil the hardness conditions according to the invention.
Another particularly preferred embodiment of the dosage form according to the invention comprises a vertical or horizontal arrangement of the layers of subunits (X) and (Y) and at least one push layer (p) arranged therebetween, and optionally a separation layer (Z), in which dosage form the entirety of the free surface of layer structure consisting of subunits (X) and (Y), the push layer and the optionally present separation layer (Z) is provided with a semipermeable coating (E), which is permeable to a release medium, i.e. conventionally a physiological liquid, but substantially impermeable to the active ingredient and to component (c) and/or (d) and/or (f), and wherein this coating (E) comprises at least one opening for release of the active ingredient in the area of subunit (X).
A corresponding dosage form is known to the person skilled in the art, for example under the name oral osmotic therapeutic system (OROS), as are suitable materials and methods for the production thereof, inter alia from U.S. Pat. No. 4,612,008, U.S. Pat. No. 4,765,989 and U.S. Pat. No. 4,783,337. The corresponding descriptions are hereby introduced as a reference and are deemed to be part of the disclosure.
In a further preferred embodiment, the subunit (X) of the dosage form according to the invention is in the form of a tablet, the edge face of which and optionally one of the two main faces is covered with a barrier layer (Z′) containing component (c) and/or (d) and/or (f).
The person skilled in the art will understand that the auxiliary substances of the subunit(s) (X) or (Y) and of the optionally present separation layer(s) (Z) and/or of the barrier layer(s) (Z′) used in formulating the dosage form according to the invention will vary as a function of the arrangement thereof in the dosage form according to the invention, the mode of administration and as a function of the particular active ingredient of the optionally present components (a) and/or (b) and/or (e) and of component (c) and/or (d) and/or (f). The materials which have the requisite properties are in each case known per se to the person skilled in the art.
If release of component (c) and/or (d) and/or (f) from subunit (Y) of the dosage form according to the invention is prevented with the assistance of a cover, preferably a barrier layer, the subunit may consist of conventional materials known to the person skilled in the art, providing that it contains at least one polymer (C) to fulfil the hardness condition of the dosage form according to the invention.
If a corresponding barrier layer (Z′) is not provided to prevent release of component (c) and/or (d) and/or (f), the materials of the subunits should be selected such that release of the particular component (c) and/or (d) from subunit (Y) is virtually ruled out. The materials which are stated below to be suitable for production of the barrier layer may preferably be used for this purpose. The materials for the separation layer and/or barrier layer must contain at least one polymer (C) in order to fulfil the hardness conditions.
Preferred materials are those which are selected from the group consisting of alkylcelluloses, hydroxyalkylcelluloses, glucans, scleroglucans, mannans, xanthans, copolymers of poly[bis(p-carboxyphenoxy)propane and sebacic acid, preferably in a molar ratio of 20:80 (commercially available under the name Polifeprosan 20®), carboxymethylcelluloses, cellulose ethers, cellulose esters, nitrocelluloses, polymers based on (meth)acrylic acid and the esters thereof, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, halogenated polyvinyls, polyglycolides, polysiloxanes and polyurethanes and the copolymers thereof.
Particularly suitable materials may be selected from the group consisting of methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose acetate, cellulose propionate (of low, medium or high molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethylcellulose, cellulose triacetate, sodium cellulose sulfate, polymethyl methacrylate, polyethyl methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, polyhexyl methacrylate, polyisodecyl methacrylate, polylauryl methacrylate, polyphenyl methacrylate, polymethyl acrylate, polyisopropyl acrylate, polyisobutyl acrylate, polyoctadecyl acrylate, polyethylene, low density polyethylene, high density polyethylene, polypropylene, polyethylene glycol, polyethylene oxide, polyethylene terephthalate, polyvinyl alcohol, polyvinyl isobutyl ether, polyvinyl acetate and polyvinyl chloride.
Particularly suitable copolymers may be selected from the group consisting of copolymers of butyl methacrylate and isobutyl methacrylate, copolymers of methyl vinyl ether and maleic acid with high molecular weight, copolymers of methyl vinyl ether and maleic acid monoethyl ester, copolymers of methyl vinyl ether and maleic anhydride and copolymers of vinyl alcohol and vinyl acetate.
Further materials which are particularly suitable for formulating the barrier layer are starch-filled polycaprolactone (WO98/20073), aliphatic polyesteramides (DE 19 753 534 A1, DE 19 800 698 A1, EP 0 820 698 A1), aliphatic and aromatic polyester urethanes (DE 19822979), polyhydroxyalkanoates, in particular polyhydroxybutyrates, polyhydroxyvalerates, casein (DE 4 309 528), polylactides and copolylactides (EP 0 980 894 A1). The corresponding descriptions are hereby introduced as a reference and are deemed to be part of the disclosure.
The above-stated materials may optionally be blended with further conventional auxiliary substances known to the person skilled in the art, preferably selected from the group consisting of glyceryl monostearate, semi-synthetic triglyceride derivatives, semi-synthetic glycerides, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyvinylpyrrolidone, gelatine, magnesium stearate, stearic acid, sodium stearate, talcum, sodium benzoate, boric acid and colloidal silica, fatty acids, substituted triglycerides, glycerides, polyoxyalkylene glycols and the derivatives thereof.
If the dosage form according to the invention comprises a separation layer (Z′), said layer, like the uncovered subunit (Y), may preferably consist of the above-stated materials described for the barrier layer. The person skilled in the art will understand that release of the active ingredient or of component (c) and/or (d) from the particular subunit may be controlled by the thickness of the separation layer.
The dosage form according to the invention may comprise one or more active ingredients at least partially in controlled release form, wherein controlled release may be achieved with the assistance of conventional materials and methods known to the person skilled in the art, for example by embedding the active ingredient in a controlled release matrix or by the application of one or more controlled release coatings. Active ingredient release must, however, be controlled such that the above-stated conditions are fulfilled in each case, for example that, in the event of correct administration of the dosage form, the active ingredient or active ingredients are virtually completely released before the optionally present component (c) and/or (d) can exert an impairing effect.
Controlled release from the dosage form according to the invention is preferably achieved by embedding the active ingredient in a matrix. The auxiliary substances acting as matrix materials control active ingredient release. Matrix materials may, for example, be hydrophilic, gel-forming materials, from which active ingredient release proceeds mainly by diffusion, or hydrophobic materials, from which active ingredient release proceeds mainly by diffusion from the pores in the matrix.
Physiologically acceptable, hydrophobic materials which are known to the person skilled in the art may be used as matrix materials. Polymers, particularly preferably cellulose ethers, cellulose esters and/or acrylic resins are preferably used as hydrophilic matrix materials. Ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and/or the derivatives thereof, such as the salts, amides or esters thereof are very particularly preferably used as matrix materials.
Matrix materials prepared from hydrophobic materials, such as hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding esters or ethers or mixtures thereof are also preferred. Mono- or diglycerides of C12-C30 fatty acids and/or C12-C30 fatty alcohols and/or waxes or mixtures thereof are particularly preferably used as hydrophobic materials.
It is also possible to use mixtures of the above-stated hydrophilic and hydrophobic materials as matrix materials.
Component (C) and the optionally present component (D), which serve to achieve the breaking strength of at least 500 N which is necessary according to the invention may furthermore also optionally serve as additional matrix materials.
If the dosage form according to the invention is intended for oral administration, it may also preferably comprise a coating which is resistant to gastric juices and dissolves as a function of the pH value of the release environment. By means of this coating, it is possible to ensure that the dosage form according to the invention passes through the stomach undissolved and the active ingredient is only released in the intestines. The coating which is resistant to gastric juices preferably dissolves at a pH value of between 5 and 7.5.
Corresponding materials and methods for the controlled release of active ingredients and for the application of coatings which are resistant to gastric juices are known to the person skilled in the art, for example from “Coated Pharmaceutical Dosage Forms—Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials” by Kurt H. Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart, 1st edition, 1998, Medpharm Scientific Publishers. The corresponding literature description is hereby introduced as a reference and is deemed to be part of the disclosure.
Method for Determining Breaking Strength
- A) In order to verify whether a polymer may be used as component (C), the polymer is pressed to form a tablet with a diameter of 10 mm and a height of 5 mm using a force of 150 N at a temperature which at least corresponds to the softening point of the polymer and is determined with the assistance of a DSC diagram of the polymer. Using tablets produced in this manner, breaking strength is determined with the apparatus described below in accordance with the method for determining the breaking strength of tablets published in the European Pharmacopoeia 1997, page 143-144, method no. 2.9.8. The apparatus used for the measurement is a series 3300 universal tester, single column benchtop model no. 3345 from Instron®, Canton, Mass., USA. The clamping tool used is a pressure piston with a diameter of 25 mm, which can be subjected to a load of up to 1 kN (item no. 2501-3 from Instron®).
- An Instron® universal tester, single column benchtop model no. 5543, with the above-stated clamping tool may also be used to carry out the measurement.
- The tablets deemed to be resistant to breaking under a specific load include not only those which have not broken but also those which may have suffered plastic deformation under the action of the force.
- Providing that the dosage form is in tablet form, breaking strength may be determined using the same measurement method.
The following Examples illustrate the invention purely by way of example and without restricting the general concept of the invention.
EXAMPLESTramadol hydrochloride was used as the active ingredient in a series of Examples. Tramadol hydrochloride was used, despite tramadol not being an active ingredient which conventionally has abuse potential, because it is not governed by German narcotics legislation, so simplifying the experimental work. Tramadol is moreover a member of the opioid class with excellent water solubility.
Example 1
Tramadol hydrochloride and polyethylene oxide powder were mixed in a free-fall mixer. A tabletting tool with top punch, bottom punch and die for tablets with a diameter of 10 mm and a radius of curvature of 8 mm was heated to 80° C. in a heating cabinet. 300 mg portions of the powder mixture were pressed with the heated tool, wherein pressure was maintained for at least 15 seconds by clamping the tabletting tool in a vice.
The breaking strength of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not break when exposed to a force of 500 N.
The tablet could not be comminuted using a hammer, nor with the assistance of a mortar and pestle.
In vitro release of the active ingredient from the preparation was determined in a paddle stirrer apparatus in accordance with Pharm. Eur. The temperature of the release medium was 37° C. and the rotational speed of the stirrer 75 min−1. At the beginning of the investigation, each tablet was placed in a 600 ml portion of artificial gastric juice, pH 1.2. After 30 minutes, the pH value was increased to 2.3 by addition of alkali solution, after a further 90 minutes to pH 6.5 and after a further 60 minutes to pH 7.2. The released quantity of active ingredient present in the dissolution medium at each point in time was determined by spectrophotometry.
300 mg portions of the powder mixture from Example 1 were heated to 80° C. and in placed in the die of the tabletting tool. Pressing was then performed. The tablet exhibits the same properties such as the tablet in Example 1.
Example 3
Tramadol hydrochloride and the above-stated components were mixed in a free-fall mixer. A tabletting tool with top punch, bottom punch and die for tablets with a diameter of 7 mm was heated to 80° C. in a heating cabinet. 150 mg portions of the powder mixture were pressed with the heated tool, wherein pressure was maintained for at least 15 seconds by clamping the tabletting tool in a vice.
The breaking strength of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not break when exposed to a force of 500 N.
In vitro release of the active ingredient was determined as in Example 1 and was:
Tramadol hydrochloride, xanthan and polyethylene oxide were mixed in a free-fall mixer. A tabletting tool with top punch, bottom punch and die for tablets with a diameter of 10 mm and a radius of curvature of 8 mm was heated to 80° C. in a heating cabinet. 300 mg portions of the powder mixture were pressed with the heated tool, wherein pressure was maintained for at least 15 seconds by clamping the tabletting tool in a vice.
The breaking strength of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not break when exposed to a force of 500 N. The tablets did suffer a little plastic deformation.
In vitro release of the active ingredient was determined as in Example 1 and was:
The tablets could be cut up with a knife into pieces of an edge length of as small as approx. 2 mm. No further comminution proceeding as far as pulverisation was possible. When the pieces are combined with water, a highly viscous gel is formed. Only with great difficulty could the gel be pressed through a 0.9 mm injection cannula. When the gel was injected into water, the gel did not spontaneously mix with water, but remained visually distinguishable.
Example 5
Tramadol hydrochloride, xanthan and polyethylene oxide were mixed in a free-fall mixer. A tabletting tool with a top punch, bottom punch and die for oblong tablets 10 mm in length and 5 mm in width was heated to 90° C. in a heating cabinet. 150 mg portions of the powder mixture were pressed with the heated tool, wherein pressure was maintained for at least 15 seconds by clamping the tabletting tool in a vice.
The breaking strength of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not break when exposed to a force of 500 N. The tablets did suffer a little plastic deformation.
In vitro release of the active ingredient was determined as in Example 1 and was:
The tablets could be cut up into pieces of an edge length of as small as approx. 2 mm, but could not be pulverised. When the pieces are combined with water, a highly viscous gel is formed. Only with great difficulty could the gel be pressed through a 0.9 mm injection cannula. When the gel was injected into water, the gel did not spontaneously mix with water, but remained visually distinguishable.
Example 6A tablet with the following composition was produced as described in Example 1:
Release of the active ingredient was determined as follows:
In vitro release of the active ingredient from the preparation was determined in a paddle stirrer apparatus in accordance with Pharm. Eur. The temperature of the release medium was 37° C. and the rotational speed 75 rpm. The phosphate buffer, pH 6.8, described in DSP served as the release medium. The quantity of active ingredient present in the solvent at the particular time of testing was determined by spectrophotometry.
The breaking strength of the tablets was determined with the stated apparatus in accordance with the stated method. The tablets did not break when exposed to a force of 500 N.
The tablets could be cut up into pieces of an edge length of as small as approx. 2 mm, but could not be pulverised. When the pieces are combined with water, a highly viscous gel is formed. Only with great difficulty could the gel be pressed through a 0.9 mm injection cannula. When the gel was injected into water, the gel did not spontaneously mix with water, but remained visually distinguishable.
Claims
1. An abuse-proofed, thermoformed dosage form having a breaking strength of at least 500 N, said dosage form being in the form of a tablet obtained by a process comprising:
- a) mixing: i) an opioid or a physiologically acceptable salt thereof; ii) optionally physiologically acceptable substances (B); iii) at least one polyalkylene oxide (C) having a molecular weight of 1-15 million according to rheological measurements, wherein the content of component (C) is at least 60 wt. %, relative to the total weight of the tablet; and iv) optionally at least one wax (D); to form a resultant mixture;
- b) press-forming the resultant mixture to form a press-formed product; and
- c) exposing the press-formed product to heat to yield the dosage form.
2. A dosage form according to claim 1, wherein the opioid or physiologically acceptable salt thereof is oxycodone or a physiologically acceptable salt thereof.
3. A method of treating pain in a patient suffering therefrom, said method comprising administering to said patient a dosage form according to claim 1.
4. A dosage form according to claim 1, wherein the opioid or physiologically acceptable salt thereof is morphine or a physiologically acceptable salt thereof.
5. A method according to claim 3, wherein the opioid or physiologically acceptable salt thereof is oxycodone or a physiologically acceptable salt thereof.
6. A method according to claim 3, wherein the opioid or physiologically acceptable salt thereof is morphine or a physiologically acceptable salt thereof.
2524855 | October 1950 | Schnider et al. |
2806033 | September 1957 | Lewenstein et al. |
2987445 | June 1961 | Levesque |
3332950 | July 1967 | Blumberg et al. |
3370035 | February 1968 | Ogura et al. |
3652589 | March 1972 | Flick et al. |
3806603 | April 1974 | Gaunt et al. |
3865108 | February 1975 | Hartop |
3941865 | March 2, 1976 | Miller et al. |
3966747 | June 29, 1976 | Monkovic et al. |
3980766 | September 14, 1976 | Shaw et al. |
4002173 | January 11, 1977 | Manning et al. |
4014965 | March 29, 1977 | Stube et al. |
4070494 | January 24, 1978 | Hoffmeister et al. |
4070497 | January 24, 1978 | Wismer et al. |
4175119 | November 20, 1979 | Porter |
4200704 | April 29, 1980 | Stanley et al. |
4207893 | June 17, 1980 | Michaels |
4262017 | April 14, 1981 | Kuipers et al. |
4343789 | August 10, 1982 | Kawata et al. |
4353887 | October 12, 1982 | Hess et al. |
4404183 | September 13, 1983 | Kawata et al. |
4427681 | January 24, 1984 | Munshi et al. |
4427778 | January 24, 1984 | Zabriskie |
4457933 | July 3, 1984 | Gordon et al. |
4462941 | July 31, 1984 | Lee et al. |
4473640 | September 25, 1984 | Combie et al. |
4483847 | November 20, 1984 | Augart |
4485211 | November 27, 1984 | Okamoto |
4529583 | July 16, 1985 | Porter |
4599342 | July 8, 1986 | La Hann |
4603143 | July 29, 1986 | Schmidt |
4612008 | September 16, 1986 | Wong et al. |
4629621 | December 16, 1986 | Snipes |
4667013 | May 19, 1987 | Reichle |
4690822 | September 1, 1987 | Uemura |
4713243 | December 15, 1987 | Schiraldi et al. |
4744976 | May 17, 1988 | Snipes et al. |
4764378 | August 16, 1988 | Keitn et al. |
4765989 | August 23, 1988 | Wong et al. |
4774074 | September 27, 1988 | Snipes |
4774092 | September 27, 1988 | Hamilton |
4783337 | November 8, 1988 | Wong et al. |
4806337 | February 21, 1989 | Snipes et al. |
RE33093 | October 17, 1989 | Schiraldi et al. |
4880585 | November 14, 1989 | Klimesch et al. |
4892778 | January 9, 1990 | Theeuwes et al. |
4892889 | January 9, 1990 | Kirk |
4940556 | July 10, 1990 | MacFarlane et al. |
4954346 | September 4, 1990 | Sparta et al. |
4957668 | September 18, 1990 | Plackard et al. |
4957681 | September 18, 1990 | Klimesch et al. |
4960814 | October 2, 1990 | Wu et al. |
4992278 | February 12, 1991 | Khanna |
4992279 | February 12, 1991 | Palmer et al. |
5004601 | April 2, 1991 | Snipes |
5051261 | September 24, 1991 | McGinty |
5073379 | December 17, 1991 | Klimesch et al. |
5082668 | January 21, 1992 | Wong et al. |
5126151 | June 30, 1992 | Bodor et al. |
5139790 | August 18, 1992 | Snipes |
5145944 | September 8, 1992 | Steinmann |
5149538 | September 22, 1992 | Granger et al. |
5169645 | December 8, 1992 | Shukla et al. |
5190760 | March 2, 1993 | Baker |
5198226 | March 30, 1993 | MacFarlane et al. |
5200194 | April 6, 1993 | Edgren et al. |
5200197 | April 6, 1993 | Wright et al. |
5211892 | May 18, 1993 | Gueret |
5225417 | July 6, 1993 | Dappen |
5227157 | July 13, 1993 | McGinity et al. |
5229164 | July 20, 1993 | Pins et al. |
5273758 | December 28, 1993 | Royce |
5326852 | July 5, 1994 | Fujikake |
5350741 | September 27, 1994 | Takada |
5378462 | January 3, 1995 | Boedecker et al. |
5387420 | February 7, 1995 | Mitchell |
5427798 | June 27, 1995 | Ludgwig et al. |
RE34990 | July 4, 1995 | Khanna et al. |
5458887 | October 17, 1995 | Chen et al. |
5460826 | October 24, 1995 | Merrill et al. |
5472943 | December 5, 1995 | Crain et al. |
5508042 | April 16, 1996 | Oshlack et al. |
5552159 | September 3, 1996 | Mueller et al. |
5556640 | September 17, 1996 | Ito et al. |
5562920 | October 8, 1996 | Demmer et al. |
5591452 | January 7, 1997 | Miller et al. |
5593694 | January 14, 1997 | Hayashida et al. |
5601842 | February 11, 1997 | Bartholomaeus |
5620697 | April 15, 1997 | Tormala et al. |
5679685 | October 21, 1997 | Cincotta et al. |
5681517 | October 28, 1997 | Metzger |
5707636 | January 13, 1998 | Rodriguez et al. |
5741519 | April 21, 1998 | Rosenberg et al. |
5792474 | August 11, 1998 | Rauchfuss |
5801201 | September 1, 1998 | Gradums et al. |
5811126 | September 22, 1998 | Krishanamurthy |
5849240 | December 15, 1998 | Miller et al. |
5866164 | February 2, 1999 | Kuczynski et al. |
5900425 | May 4, 1999 | Kanikanti et al. |
5908850 | June 1, 1999 | Zeitlin et al. |
5914132 | June 22, 1999 | Kelm et al. |
5916584 | June 29, 1999 | O'Donoghue et al. |
5928739 | July 27, 1999 | Pophusen et al. |
5939099 | August 17, 1999 | Grabowski et al. |
5945125 | August 31, 1999 | Kim |
5948787 | September 7, 1999 | Merill et al. |
5962488 | October 5, 1999 | Lang |
5965161 | October 12, 1999 | Oshlack et al. |
5968925 | October 19, 1999 | Knidlberger |
6001391 | December 14, 1999 | Zeidler et al. |
6009390 | December 28, 1999 | Gupta et al. |
6009690 | January 4, 2000 | Rosenberg et al. |
6051253 | April 18, 2000 | Zettler et al. |
6071970 | June 6, 2000 | Mueller et al. |
6077538 | June 20, 2000 | Merrill et al. |
6090411 | July 18, 2000 | Pillay et al. |
6093420 | July 25, 2000 | Baichwal |
6096339 | August 1, 2000 | Ayer et al. |
6117453 | September 12, 2000 | Seth et al. |
6120802 | September 19, 2000 | Breitenbach et al. |
6133241 | October 17, 2000 | Bok et al. |
6183781 | February 6, 2001 | Burke |
6235825 | May 22, 2001 | Yoshida et al. |
6228863 | May 8, 2001 | Palermo et al. |
6238697 | May 29, 2001 | Kumar et al. |
6245357 | June 12, 2001 | Edgren et al. |
6248737 | June 19, 2001 | Buschmann et al. |
6251430 | June 26, 2001 | Zhang et al. |
6254887 | July 3, 2001 | Miller et al. |
6261599 | July 17, 2001 | Oshlack |
6290990 | September 18, 2001 | Grabowski et al. |
6306438 | October 23, 2001 | Oshlack et al. |
6309668 | October 30, 2001 | Bastin et al. |
6318650 | November 20, 2001 | Breitenbach et al. |
6322819 | November 27, 2001 | Burnside et al. |
6326027 | December 4, 2001 | Miller et al. |
6335035 | January 1, 2002 | Drizen et al. |
6337319 | January 8, 2002 | Wang |
6340475 | January 22, 2002 | Shell et al. |
6344215 | February 5, 2002 | Bettman et al. |
6344535 | February 5, 2002 | Timmermann et al. |
6348469 | February 19, 2002 | Seth |
6355656 | March 12, 2002 | Zeitlin et al. |
6375957 | April 23, 2002 | Kaiko et al. |
6375963 | April 23, 2002 | Repka et al. |
6387995 | May 14, 2002 | Sojka |
6399100 | June 4, 2002 | Clancy et al. |
6419954 | July 16, 2002 | Chu et al. |
6436441 | August 20, 2002 | Sako et al. |
6455052 | September 24, 2002 | Marcussen et al. |
6461644 | October 8, 2002 | Jackson et al. |
6488939 | December 3, 2002 | Zeidler et al. |
6488962 | December 3, 2002 | Berner et al. |
6488963 | December 3, 2002 | McGinity et al. |
6534089 | March 18, 2003 | Ayer et al. |
6547977 | April 15, 2003 | Yan et al. |
6547997 | April 15, 2003 | Breithenbach et al. |
6562375 | May 13, 2003 | Sako et al. |
6569506 | May 27, 2003 | Jerdee et al. |
6572889 | June 3, 2003 | Guo |
6592901 | July 15, 2003 | Durig et al. |
6623754 | September 23, 2003 | Guo et al. |
6635280 | October 21, 2003 | Shell et al. |
6696088 | February 24, 2004 | Oshlack et al. |
6699503 | March 2, 2004 | Sako et al. |
6723340 | April 20, 2004 | Gusler et al. |
6723343 | April 20, 2004 | Kugelmann |
6733783 | May 11, 2004 | Oshlack et al. |
6753009 | June 22, 2004 | Luber et al. |
6821588 | November 23, 2004 | Hammer et al. |
6979722 | December 27, 2005 | Hamamoto et al. |
7074430 | July 11, 2006 | Miller et al. |
7129248 | October 31, 2006 | Chapman et al. |
7141250 | November 28, 2006 | Oshlack et al. |
7157103 | January 2, 2007 | Sackler |
7176251 | February 13, 2007 | Bastioli et al. |
RE39593 | April 24, 2007 | Buschmann et al. |
7201920 | April 10, 2007 | Kumar et al. |
7214385 | May 8, 2007 | Gruber |
7230005 | June 12, 2007 | Shafer et al. |
7300668 | November 27, 2007 | Pryce et al. |
7332182 | February 19, 2008 | Sackler |
7388068 | June 17, 2008 | Falk et al. |
7399488 | July 15, 2008 | Hirsh et al. |
7510726 | March 31, 2009 | Kumar et al. |
7674799 | March 9, 2010 | Chapman et al. |
7674800 | March 9, 2010 | Chapman et al. |
7683072 | March 23, 2010 | Chapman et al. |
7776314 | August 17, 2010 | Bartholomaus et al. |
7842307 | November 30, 2010 | Oshlack et al. |
7851482 | December 14, 2010 | Dung et al. |
7932258 | April 26, 2011 | Petereit et al. |
7939543 | May 10, 2011 | Kupper |
7968119 | June 28, 2011 | Farrell |
7994364 | August 9, 2011 | Fischer et al. |
8075872 | December 13, 2011 | Arkenau-Maric |
8101630 | January 24, 2012 | Kumar et al. |
8114383 | February 14, 2012 | Bartholomaeus et al. |
8114384 | February 14, 2012 | Arkenau et al. |
8114838 | February 14, 2012 | Marchionni |
8192722 | June 5, 2012 | Arkenau-Maric et al. |
8202542 | June 19, 2012 | Mehta et al. |
8309060 | November 13, 2012 | Bartholomeus et al. |
8309122 | November 13, 2012 | Kao et al. |
8323889 | December 4, 2012 | Arkenau-Maric et al. |
8329216 | December 11, 2012 | Kao et al. |
8337888 | December 25, 2012 | Wright et al. |
8383152 | February 26, 2013 | Jans et al. |
8420056 | April 16, 2013 | Arkenau-Maric et al. |
8445023 | May 21, 2013 | Guimberteau et al. |
8722086 | May 13, 2014 | Arkenau-Maric et al. |
8858963 | October 14, 2014 | Devarakonda et al. |
8901113 | December 2, 2014 | Leech et al. |
9192578 | November 24, 2015 | McGinity et al. |
9629807 | April 25, 2017 | Arkenau-Maric et al. |
9675610 | June 13, 2017 | Bartholomaeus et al. |
9737490 | August 22, 2017 | Barnscheid et al. |
20010038852 | November 8, 2001 | Kolter et al. |
20020012701 | January 31, 2002 | Kolter et al. |
20020015730 | February 7, 2002 | Hoffmann et al. |
20020187192 | December 12, 2002 | Joshi et al. |
20020051820 | May 2, 2002 | Shell et al. |
20020114838 | August 22, 2002 | Ayer et al. |
20020132359 | September 19, 2002 | Waterman |
20020132395 | September 19, 2002 | Iyer et al. |
20020176888 | November 28, 2002 | Bartholomaeus et al. |
20020192277 | December 19, 2002 | Oshlack et al. |
20030008409 | January 9, 2003 | Spearman et al. |
20030015814 | January 23, 2003 | Krull et al. |
20030017532 | January 23, 2003 | Biswas et al. |
20030021546 | January 30, 2003 | Sato |
20030044458 | March 6, 2003 | Wright et al. |
20030044464 | March 6, 2003 | Ziegler et al. |
20030064099 | April 3, 2003 | Oshlack et al. |
20030068276 | April 10, 2003 | Hughes et al. |
20030068370 | April 10, 2003 | Sackler et al. |
20030068371 | April 10, 2003 | Oshlack et al. |
20030068375 | April 10, 2003 | Wright et al. |
20030068392 | April 10, 2003 | Sackler |
20030069263 | April 10, 2003 | Breder et al. |
20030077297 | April 24, 2003 | Chen et al. |
20030091630 | May 15, 2003 | Louie-Helm et al. |
20030092724 | May 15, 2003 | Huaihung et al. |
20030104052 | June 5, 2003 | Berner et al. |
20030104053 | June 5, 2003 | Gusler et al. |
20030118641 | June 26, 2003 | Maloney et al. |
20030124185 | July 3, 2003 | Oshlack et al. |
20030125347 | July 3, 2003 | Anderson et al. |
20030129230 | July 10, 2003 | Baichwal et al. |
20030133985 | July 17, 2003 | Louie-Helm et al. |
20030143269 | July 31, 2003 | Oshlack et al. |
20030152622 | August 14, 2003 | Louie-Helm et al. |
20030158242 | August 21, 2003 | Kugelmann |
20030158265 | August 21, 2003 | Radhakrishnan et al. |
20030175326 | September 18, 2003 | Thombre |
20030198677 | October 23, 2003 | Pryce Lewis et al. |
20030215508 | November 20, 2003 | Davis et al. |
20030232895 | December 18, 2003 | Omidian et al. |
20040010000 | January 15, 2004 | Ayer et al. |
20040011806 | January 22, 2004 | Luciano et al. |
20040049079 | March 11, 2004 | Murray et al. |
20040052731 | March 18, 2004 | Hirsh et al. |
20040052844 | March 18, 2004 | Hsiao et al. |
20040081694 | April 29, 2004 | Oshlack |
20040091528 | May 13, 2004 | Rogers et al. |
20040126428 | July 1, 2004 | Hughes et al. |
20040131671 | July 8, 2004 | Zhang et al. |
20040156899 | August 12, 2004 | Louie-Helm et al. |
20040170567 | September 2, 2004 | Sackler |
20040170680 | September 2, 2004 | Oshlack et al. |
20040185105 | September 23, 2004 | Berner et al. |
20040213845 | October 28, 2004 | Sugihara |
20040213848 | October 28, 2004 | Li et al. |
20040253310 | December 16, 2004 | Fischer et al. |
20050015730 | January 20, 2005 | Gunturi et al. |
20050031546 | February 10, 2005 | Bartholomaeus et al. |
20050058706 | March 17, 2005 | Bartholomaeus et al. |
20050063214 | March 24, 2005 | Takashima |
20050089475 | April 28, 2005 | Gruber |
20050089569 | April 28, 2005 | Bar-Shalom |
20050095291 | May 5, 2005 | Oshlack et al. |
20050106249 | May 19, 2005 | Hwang et al. |
20050112067 | May 26, 2005 | Kumar et al. |
20050127555 | June 16, 2005 | Gusik et al. |
20050152843 | July 14, 2005 | Bartholomaeus et al. |
20050181046 | August 18, 2005 | Oshlack et al. |
20050186139 | August 25, 2005 | Bartholomaeus et al. |
20050191244 | September 1, 2005 | Bartholomaeus et al. |
20050191352 | September 1, 2005 | Hayes |
20050192333 | September 1, 2005 | Hinze et al. |
20050214223 | September 29, 2005 | Bartholomaeus et al. |
20050220877 | October 6, 2005 | Patel |
20050222188 | October 6, 2005 | Chapman et al. |
20050236741 | October 27, 2005 | Arkenau et al. |
20050245556 | November 3, 2005 | Brogman et al. |
20050266084 | December 1, 2005 | Li et al. |
20060002859 | January 5, 2006 | Arkenau et al. |
20060002860 | January 5, 2006 | Bartholomaus et al. |
20060004034 | January 5, 2006 | Hinze et al. |
20060009478 | January 12, 2006 | Friedman et al. |
20060017916 | January 26, 2006 | Clarke et al. |
20060039864 | February 23, 2006 | Bartholomaus et al. |
20060073102 | April 6, 2006 | Huaihung et al. |
20060099250 | May 11, 2006 | Tian et al. |
20060104909 | May 18, 2006 | Vaghefi |
20060182801 | August 17, 2006 | Breder et al. |
20060188447 | August 24, 2006 | Arkenau-Maric et al. |
20060193782 | August 31, 2006 | Bartholomaus et al. |
20060193914 | August 31, 2006 | Ashworth et al. |
20060194759 | August 31, 2006 | Eidelson |
20060194826 | August 31, 2006 | Oshlack et al. |
20060240105 | October 26, 2006 | Devane et al. |
20060240110 | October 26, 2006 | Kiick et al. |
20060269603 | November 30, 2006 | Brown Miller et al. |
20070003616 | January 4, 2007 | Arkenau-Maric et al. |
20070003617 | January 4, 2007 | Fischer et al. |
20070020188 | January 25, 2007 | Sackler |
20070020335 | January 25, 2007 | Chen et al. |
20070042044 | February 22, 2007 | Fischer et al. |
20070048228 | March 1, 2007 | Arkenau-Maric et al. |
20070065365 | March 22, 2007 | Kugelmann et al. |
20070092573 | April 26, 2007 | Joshi et al. |
20070183979 | August 9, 2007 | Arkenau-Maric et al. |
20070183980 | August 9, 2007 | Arkenau-Maric et al. |
20070184117 | August 9, 2007 | Gregory et al. |
20070190142 | August 16, 2007 | Breitenbach et al. |
20070196396 | August 23, 2007 | Pilgaonkar et al. |
20070196481 | August 23, 2007 | Amidon et al. |
20070224129 | September 27, 2007 | Guimberteau et al. |
20070231268 | October 4, 2007 | Emigh et al. |
20070259045 | November 8, 2007 | Mannion et al. |
20070264327 | November 15, 2007 | Kumar et al. |
20070269505 | November 22, 2007 | Flath et al. |
20070292508 | December 20, 2007 | Szamosi et al. |
20080020032 | January 24, 2008 | Crowley et al. |
20080063725 | March 13, 2008 | Guimberteau et al. |
20080069871 | March 20, 2008 | Vaughn et al. |
20080075669 | March 27, 2008 | Soscia et al. |
20080075768 | March 27, 2008 | Vaughn et al. |
20080081290 | April 3, 2008 | Wada et al. |
20080085304 | April 10, 2008 | Baichwal et al. |
20080131503 | June 5, 2008 | Holm et al. |
20080145429 | June 19, 2008 | Leyenecker et al. |
20080152595 | June 26, 2008 | Emigh et al. |
20080181932 | July 31, 2008 | Bortz et al. |
20080220079 | September 11, 2008 | Chen |
20080233178 | September 25, 2008 | Reidenberg et al. |
20080234352 | September 25, 2008 | Fischer et al. |
20080247959 | October 9, 2008 | Bartholomaus et al. |
20080248113 | October 9, 2008 | Bartholomaus et al. |
20080260836 | October 23, 2008 | Boyd |
20080280975 | November 13, 2008 | Badul |
20080311049 | December 18, 2008 | Arkenau-Maric et al. |
20080311187 | December 18, 2008 | Ashworth et al. |
20080311197 | December 18, 2008 | Arkenau-Maric et al. |
20080311205 | December 18, 2008 | Habib et al. |
20080312264 | December 18, 2008 | Arkenau-Maric et al. |
20080317695 | December 25, 2008 | Everaert et al. |
20080317854 | December 25, 2008 | Arkenau et al. |
20090004267 | January 1, 2009 | Arkenau-Maric et al. |
20090005408 | January 1, 2009 | Arkenau-Maric et al. |
20090011016 | January 8, 2009 | Cailly-Dufestel et al. |
20090017121 | January 15, 2009 | Berner et al. |
20090022798 | January 22, 2009 | Rosenberg et al. |
20090081287 | March 26, 2009 | Wright et al. |
20090081290 | March 26, 2009 | McKenna et al. |
20090117191 | May 7, 2009 | Brown Miller et al. |
20090202634 | August 13, 2009 | Jans et al. |
20090215808 | August 27, 2009 | Yum et al. |
20090232887 | September 17, 2009 | Odidi et al. |
20090253730 | October 8, 2009 | Kumar et al. |
20090317355 | December 24, 2009 | Roth et al. |
20090318395 | December 24, 2009 | Schramm et al. |
20100015223 | January 21, 2010 | Cailly-Deufestel et al. |
20100035886 | February 11, 2010 | Cincotta et al. |
20100047345 | February 25, 2010 | Crowley et al. |
20100092553 | April 15, 2010 | Guimberteau et al. |
20100098758 | April 22, 2010 | Bartholomaus et al. |
20100099696 | April 22, 2010 | Soscia et al. |
20100104638 | April 29, 2010 | Dai et al. |
20100151028 | June 17, 2010 | Ashworth et al. |
20100168148 | July 1, 2010 | Wright et al. |
20100172989 | July 8, 2010 | Roth et al. |
20100203129 | August 12, 2010 | Anderson et al. |
20100221322 | September 2, 2010 | Bartholomaus et al. |
20100249045 | September 30, 2010 | Babul |
20100260833 | October 14, 2010 | Bartholomaus et al. |
20100280047 | November 4, 2010 | Kolter et al. |
20100291205 | November 18, 2010 | Downie et al. |
20100297229 | November 25, 2010 | Sesha |
20110020451 | January 27, 2011 | Bartholomaus et al. |
20110020454 | January 27, 2011 | Lamarca Casado |
20110038930 | February 17, 2011 | Barnscheid et al. |
20110082214 | April 7, 2011 | Faure et al. |
20110092515 | April 21, 2011 | Qiu et al. |
20110097404 | April 28, 2011 | Oshlack et al. |
20110129535 | June 2, 2011 | Mantelle |
20110159100 | June 30, 2011 | Anderson et al. |
20110187017 | August 4, 2011 | Haupts |
20110223244 | September 15, 2011 | Liversidge et al. |
20110245783 | October 6, 2011 | Stinchcomb |
20110262496 | October 27, 2011 | Desai |
20120034171 | February 9, 2012 | Arkenau-Maric et al. |
20120059065 | March 8, 2012 | Barnscheid et al. |
20120065220 | March 15, 2012 | Barnscheid et al. |
20120077879 | March 29, 2012 | Vasanthavada et al. |
20120107250 | May 3, 2012 | Bartholomaus et al. |
20120108622 | May 3, 2012 | Wright et al. |
20120135071 | May 31, 2012 | Bartholomaus et al. |
20120136021 | May 31, 2012 | Barnscheid et al. |
20120141583 | June 7, 2012 | Mannion et al. |
20120202838 | August 9, 2012 | Ghosh et al. |
20120225901 | September 6, 2012 | Leyendecker et al. |
20120231083 | September 13, 2012 | Carley et al. |
20120251637 | October 4, 2012 | Bartholomaus et al. |
20120321716 | December 20, 2012 | Vachon et al. |
20130028970 | January 31, 2013 | Schwier et al. |
20130028972 | January 31, 2013 | Schwier et al. |
20130090349 | April 11, 2013 | Gei Ler et al. |
20130129825 | May 23, 2013 | Billoet et al. |
20130129826 | May 23, 2013 | Gei Ler et al. |
20130171075 | July 4, 2013 | Arkenau-Maric et al. |
20130209557 | August 15, 2013 | Barnscheid |
20130225625 | August 29, 2013 | Barnscheid et al. |
20130251643 | September 26, 2013 | Bartholomäus et al. |
20130289062 | October 31, 2013 | Kumar et al. |
20130303623 | November 14, 2013 | Barnscheid et al. |
20130330409 | December 12, 2013 | Mohammad |
20140010874 | January 9, 2014 | Sackler |
20140079780 | March 20, 2014 | Arkenau Maric et al. |
20140080858 | March 20, 2014 | Bartholomäus et al. |
20140080915 | March 20, 2014 | Bartholomäus et al. |
20140094481 | April 3, 2014 | Fleischer et al. |
20140112984 | April 24, 2014 | Arkenau Maric et al. |
20140112989 | April 24, 2014 | Bartholomäus et al. |
20140170079 | June 19, 2014 | Arkenau Maric et al. |
20140186440 | July 3, 2014 | Han et al. |
20140275143 | September 18, 2014 | Devarakonda et al. |
20140356426 | December 4, 2014 | Barnscheid et al. |
20140356428 | December 4, 2014 | Barnscheid et al. |
20140378498 | December 25, 2014 | Devarakonda et al. |
20150017250 | January 15, 2015 | Wenig et al. |
20150030677 | January 29, 2015 | Adjei et al. |
20150064250 | March 5, 2015 | Ghebre-Sellassie et al. |
20150079150 | March 19, 2015 | Fischer et al. |
20150118300 | April 30, 2015 | Haswani et al. |
20150118302 | April 30, 2015 | Haswani et al. |
20150118303 | April 30, 2015 | Haswani et al. |
20150374630 | December 31, 2015 | Arkenau et al. |
20160089439 | March 31, 2016 | Rajagopalan |
20160175256 | June 23, 2016 | Bartholomaeus et al. |
20160184297 | June 30, 2016 | Arkenau-Maric et al. |
20160256456 | September 8, 2016 | Caruso et al. |
20160263037 | September 15, 2016 | Arkenau-Maric et al. |
20160361308 | December 15, 2016 | Bartholomaeus et al. |
20160367549 | December 22, 2016 | Bartholomaeus et al. |
20170027886 | February 2, 2017 | Bartholomaeus et al. |
046994 | December 2004 | AR |
045353 | October 2005 | AR |
049562 | August 2006 | AR |
049839 | September 2006 | AR |
053304 | May 2007 | AR |
054222 | June 2007 | AR |
054328 | June 2007 | AR |
769807 | March 2001 | AU |
2003237944 | December 2003 | AU |
2003274071 | May 2004 | AU |
2003278133 | May 2004 | AU |
2003279317 | May 2004 | AU |
2004264666 | February 2005 | AU |
2004264667 | February 2005 | AU |
2004308653 | April 2005 | AU |
2005259476 | January 2006 | AU |
2005259478 | January 2006 | AU |
2006210145 | August 2006 | AU |
2006210145 | August 2006 | AU |
2009207796 | July 2009 | AU |
2009243681 | November 2009 | AU |
2006311116 | January 2013 | AU |
P10413318 | October 2006 | BR |
P10413361 | October 2006 | BR |
P10513300 | May 2008 | BR |
P10606145 | February 2009 | BR |
0722109 | November 1965 | CA |
2082573 | May 1993 | CA |
2577233 | October 1997 | CA |
2650637 | October 1997 | CA |
2229621 | March 1998 | CA |
2317747 | July 1999 | CA |
2343234 | March 2000 | CA |
2352874 | June 2000 | CA |
2414349 | January 2002 | CA |
2456322 | February 2003 | CA |
2502965 | May 2004 | CA |
2503155 | May 2004 | CA |
2534925 | February 2005 | CA |
2534932 | February 2005 | CA |
2489855 | April 2005 | CA |
2551231 | July 2005 | CA |
2572352 | January 2006 | CA |
2572491 | January 2006 | CA |
2595954 | July 2006 | CA |
2229650 | August 2006 | CA |
2594713 | August 2006 | CA |
2595979 | August 2006 | CA |
2625055 | April 2007 | CA |
2713128 | July 2009 | CA |
2723438 | November 2009 | CA |
2595954 | January 2011 | CA |
689109 | October 1998 | CH |
20162004 | May 2005 | CL |
20172004 | May 2005 | CL |
200403308 | September 2005 | CL |
200500952 | November 2005 | CL |
200501624 | December 2005 | CL |
200501625 | June 2006 | CL |
424-2013 | March 2012 | CL |
437-2013 | March 2012 | CL |
87102755 | October 1987 | CN |
1135175 | November 1996 | CN |
1473562 | February 2004 | CN |
1980643 | April 2005 | CN |
101010071 | June 2005 | CN |
1671475 | September 2005 | CN |
101022787 | January 2006 | CN |
1863513 | November 2006 | CN |
1863514 | November 2006 | CN |
1917862 | February 2007 | CN |
1942174 | April 2007 | CN |
101011395 | August 2007 | CN |
101027044 | August 2007 | CN |
101057849 | October 2007 | CN |
101484135 | November 2007 | CN |
101091721 | December 2007 | CN |
101111232 | January 2008 | CN |
101175482 | February 2008 | CN |
101370485 | February 2009 | CN |
101394839 | March 2009 | CN |
101652128 | February 2010 | CN |
2530563 | January 1977 | DE |
4229085 | March 1994 | DE |
4309528 | September 1994 | DE |
4446470 | June 1996 | DE |
69400215 | October 1996 | DE |
19522899 | December 1996 | DE |
2808505 | January 1997 | DE |
19753534 | June 1999 | DE |
19800689 | July 1999 | DE |
19800698 | July 1999 | DE |
19822979 | December 1999 | DE |
69229881 | December 1999 | DE |
19855440 | June 2000 | DE |
19856147 | June 2000 | DE |
19940740 | March 2001 | DE |
19960494 | June 2001 | DE |
10036400 | June 2002 | DE |
69429710 | August 2002 | DE |
10250083 | December 2003 | DE |
10250084 | May 2004 | DE |
10250087 | May 2004 | DE |
10250088 | May 2004 | DE |
10336400 | March 2005 | DE |
10361596 | September 2005 | DE |
102004019916 | November 2005 | DE |
102004020220 | November 2005 | DE |
102004032049 | January 2006 | DE |
102004032051 | January 2006 | DE |
102004032103 | January 2006 | DE |
102005005446 | August 2006 | DE |
102005005449 | August 2006 | DE |
102007011485 | September 2008 | DE |
1658055 | July 2007 | DK |
1658054 | October 2007 | DK |
1515702 | January 2009 | DK |
SP066345 | August 2006 | EC |
0008131 | February 1980 | EP |
0043254 | January 1982 | EP |
0008131 | December 1982 | EP |
0177893 | April 1986 | EP |
0216453 | April 1987 | EP |
0226061 | June 1987 | EP |
0228417 | July 1987 | EP |
0229652 | July 1987 | EP |
0232877 | August 1987 | EP |
0239973 | October 1987 | EP |
0240906 | October 1987 | EP |
0261616 | March 1988 | EP |
0261616 | March 1988 | EP |
0270954 | June 1988 | EP |
0277289 | August 1988 | EP |
0293066 | November 1988 | EP |
0328775 | August 1989 | EP |
0358105 | March 1990 | EP |
0228417 | September 1990 | EP |
0229652 | October 1991 | EP |
0477135 | March 1992 | EP |
0277289 | April 1992 | EP |
0293066 | April 1993 | EP |
0270954 | May 1993 | EP |
0544144 | June 1993 | EP |
0583726 | February 1994 | EP |
0598606 | May 1994 | EP |
0636370 | February 1995 | EP |
0641195 | March 1995 | EP |
0647448 | April 1995 | EP |
0654263 | May 1995 | EP |
0661045 | July 1995 | EP |
0675710 | October 1995 | EP |
0682945 | November 1995 | EP |
0693475 | January 1996 | EP |
0820693 | January 1996 | EP |
0696598 | February 1996 | EP |
0216453 | March 1996 | EP |
0583726 | November 1996 | EP |
0756480 | February 1997 | EP |
0760654 | March 1997 | EP |
0761211 | March 1997 | EP |
0780369 | June 1997 | EP |
0785775 | July 1997 | EP |
0809488 | December 1997 | EP |
0820698 | January 1998 | EP |
0820753 | January 1998 | EP |
0857062 | August 1998 | EP |
0864324 | September 1998 | EP |
0864326 | September 1998 | EP |
0598606 | June 1999 | EP |
0675710 | August 1999 | EP |
0980894 | February 2000 | EP |
0988106 | March 2000 | EP |
1014941 | July 2000 | EP |
1070504 | January 2001 | EP |
1127871 | August 2001 | EP |
1138321 | October 2001 | EP |
1152026 | November 2001 | EP |
1138321 | January 2002 | EP |
1166776 | January 2002 | EP |
1201233 | May 2002 | EP |
0661045 | July 2002 | EP |
1250045 | October 2002 | EP |
1251120 | October 2002 | EP |
1293127 | March 2003 | EP |
1293195 | March 2003 | EP |
1293196 | March 2003 | EP |
1127871 | September 2003 | EP |
1201233 | December 2004 | EP |
1251120 | December 2004 | EP |
1492506 | January 2005 | EP |
1166776 | February 2005 | EP |
1502592 | February 2005 | EP |
1658054 | February 2005 | EP |
1658055 | February 2005 | EP |
1515702 | March 2005 | EP |
1527775 | April 2005 | EP |
1558221 | August 2005 | EP |
1558257 | August 2005 | EP |
1560585 | August 2005 | EP |
1611880 | January 2006 | EP |
1658054 | May 2006 | EP |
1138321 | January 2007 | EP |
1740161 | January 2007 | EP |
1658055 | March 2007 | EP |
1765303 | March 2007 | EP |
1786403 | May 2007 | EP |
1558221 | June 2007 | EP |
1842533 | October 2007 | EP |
1845955 | October 2007 | EP |
1845956 | October 2007 | EP |
1859789 | November 2007 | EP |
1980245 | October 2008 | EP |
1897545 | December 2008 | EP |
2131830 | December 2009 | EP |
2246063 | November 2010 | EP |
2249811 | November 2010 | EP |
2273983 | January 2011 | EP |
2402004 | January 2012 | EP |
2336571 | December 2004 | ES |
2260042 | November 2006 | ES |
2285497 | November 2007 | ES |
2288621 | January 2008 | ES |
2289542 | February 2008 | ES |
2315505 | April 2009 | ES |
1147210 | April 1969 | GB |
1567727 | May 1980 | GB |
2047095 | November 1980 | GB |
2057878 | April 1981 | GB |
2238478 | June 1991 | GB |
20070456 | June 2007 | HR |
20070272 | November 2007 | HR |
S36-022895 | November 1961 | JP |
S55162714 | December 1980 | JP |
S5659708 | May 1981 | JP |
S56169622 | December 1981 | JP |
S62240061 | October 1987 | JP |
H0249719 | February 1990 | JP |
03-501737 | April 1991 | JP |
H0517566 | January 1993 | JP |
H06507645 | September 1994 | JP |
08053331 | February 1996 | JP |
8-505076 | June 1996 | JP |
H09508410 | August 1997 | JP |
H1057450 | March 1998 | JP |
H10251149 | September 1998 | JP |
2002524150 | August 2002 | JP |
2002-275175 | September 2002 | JP |
2003125706 | May 2003 | JP |
2003526598 | September 2003 | JP |
2005506965 | March 2005 | JP |
2005515152 | May 2005 | JP |
2005534664 | November 2005 | JP |
2007501201 | January 2007 | JP |
2007501202 | January 2007 | JP |
2007513147 | May 2007 | JP |
2007533692 | November 2007 | JP |
2008024603 | February 2008 | JP |
2008504327 | February 2008 | JP |
2008528654 | July 2008 | JP |
2009523833 | June 2009 | JP |
2009531453 | September 2009 | JP |
2009537456 | October 2009 | JP |
2010534204 | November 2010 | JP |
2011504455 | February 2011 | JP |
2011506493 | March 2011 | JP |
2012515735 | July 2012 | JP |
2012528845 | November 2012 | JP |
2013536810 | September 2013 | JP |
2014505736 | March 2014 | JP |
2014528437 | October 2014 | JP |
6085307 | February 2017 | JP |
2013523780 | June 2017 | JP |
1020060069832 | June 2006 | KR |
20070039041 | April 2007 | KR |
20070111510 | November 2007 | KR |
20090085312 | August 2009 | KR |
20100111303 | October 2010 | KR |
20110016921 | February 2011 | KR |
2007000008 | March 2007 | MX |
2007000009 | March 2007 | MX |
2007009393 | August 2007 | MX |
2010008138 | August 2010 | MX |
2010012039 | November 2010 | MX |
20061054 | March 2006 | NO |
20070578 | January 2007 | NO |
20074412 | November 2007 | NO |
528302 | February 2007 | NZ |
1699440 | December 2004 | PT |
1658054 | May 2006 | PT |
1658055 | July 2007 | PT |
1515702 | December 2008 | PT |
2131244 | June 1999 | RU |
2198197 | February 2003 | RU |
2220715 | January 2004 | RU |
2328275 | May 2004 | RU |
2396944 | July 2004 | RU |
2326654 | September 2005 | RU |
2339365 | December 2007 | RU |
2354357 | December 2007 | RU |
2007103712 | September 2008 | RU |
2007103707 | November 2008 | RU |
2007132975 | April 2009 | RU |
2567723 | November 2015 | RU |
1515702 | April 2009 | SI |
1699440 | November 2009 | SI |
10612003 | January 2004 | SK |
1759445 | September 1992 | SU |
1254634 | May 2006 | TW |
WO 1980/000841 | May 1980 | WO |
WO 1989/005624 | June 1989 | WO |
WO 1990/003776 | April 1990 | WO |
WO 1993/006723 | April 1993 | WO |
WO 93/10765 | June 1993 | WO |
WO 1993/010758 | June 1993 | WO |
WO 1993/011749 | June 1993 | WO |
WO 1993/023017 | November 1993 | WO |
WO 1994/006414 | March 1994 | WO |
WO 1994/008567 | April 1994 | WO |
WO 1995/017174 | June 1995 | WO |
WO 1995/020947 | August 1995 | WO |
WO 1995/022319 | August 1995 | WO |
WO 1995/030422 | November 1995 | WO |
WO 1996/000066 | January 1996 | WO |
WO 1996/003979 | February 1996 | WO |
WO 1996/014058 | May 1996 | WO |
WO 1997/000673 | January 1997 | WO |
WO 1997/033566 | September 1997 | WO |
WO 1997/049384 | December 1997 | WO |
WO 1998/035655 | February 1998 | WO |
WO 1998/020073 | May 1998 | WO |
WO 1998/028698 | July 1998 | WO |
WO 1998/035655 | August 1998 | WO |
WO 1998/051758 | November 1998 | WO |
WO 1999/012864 | March 1999 | WO |
WO 1999/032120 | July 1999 | WO |
WO 1999/044591 | September 1999 | WO |
WO 1999/045887 | September 1999 | WO |
WO 1999/048481 | September 1999 | WO |
WO 2000/013647 | March 2000 | WO |
WO 2000/033835 | June 2000 | WO |
WO 2000/040205 | July 2000 | WO |
WO 2001/008661 | February 2001 | WO |
WO 2001/012230 | February 2001 | WO |
WO 2001/015667 | March 2001 | WO |
WO 2001/052651 | July 2001 | WO |
WO 2001/058451 | August 2001 | WO |
WO 2001/097783 | December 2001 | WO |
WO 2002/026061 | April 2002 | WO |
WO 2002/026262 | April 2002 | WO |
WO 2002/026928 | April 2002 | WO |
WO 2002/035991 | May 2002 | WO |
WO 2002/071860 | September 2002 | WO |
WO 2002/088217 | November 2002 | WO |
WO 2002/094254 | November 2002 | WO |
WO 2003/006723 | January 2003 | WO |
WO 2003/007802 | January 2003 | WO |
WO 2003/013433 | February 2003 | WO |
WO 2003/013476 | February 2003 | WO |
WO 2003/013479 | February 2003 | WO |
WO 2003/013538 | February 2003 | WO |
WO 2003/015531 | February 2003 | WO |
WO 2003/018015 | March 2003 | WO |
WO 2003/024426 | March 2003 | WO |
WO 2003/024430 | March 2003 | WO |
WO 2003/026624 | April 2003 | WO |
WO 2003/026743 | April 2003 | WO |
WO 2003/028698 | April 2003 | WO |
WO 2003/028990 | April 2003 | WO |
WO 2003/031546 | April 2003 | WO |
WO 2003/035029 | May 2003 | WO |
WO 2003/035053 | May 2003 | WO |
WO 2003/035054 | May 2003 | WO |
WO 2003/035177 | May 2003 | WO |
WO 2003/039561 | May 2003 | WO |
WO 2003/049689 | June 2003 | WO |
WO 2003/053417 | July 2003 | WO |
WO 2003/068392 | August 2003 | WO |
WO 2003/070191 | August 2003 | WO |
WO 2003/092648 | November 2003 | WO |
WO 2003/094812 | November 2003 | WO |
WO 2003/105808 | December 2003 | WO |
WO 2004/004693 | January 2004 | WO |
WO 2004/043967 | February 2004 | WO |
WO 2004/026262 | April 2004 | WO |
WO 2004/026263 | April 2004 | WO |
WO 2004/026280 | April 2004 | WO |
WO 2004/037222 | May 2004 | WO |
WO 2004/037230 | May 2004 | WO |
WO 2004/037259 | May 2004 | WO |
WO 2004/037260 | May 2004 | WO |
WO 2004/066910 | August 2004 | WO |
WO 2004/078212 | September 2004 | WO |
WO 2004/084869 | October 2004 | WO |
WO 2004/093801 | November 2004 | WO |
WO 2004/093819 | November 2004 | WO |
WO 2004/098567 | November 2004 | WO |
WO 2004/100894 | November 2004 | WO |
WO 2005/016313 | February 2005 | WO |
WO 2005/016314 | February 2005 | WO |
WO 2005/032524 | April 2005 | WO |
WO 2005/041968 | May 2005 | WO |
WO 2005/053587 | June 2005 | WO |
WO 2005/053656 | June 2005 | WO |
WO 2005/055981 | June 2005 | WO |
WO 2005/060942 | July 2005 | WO |
WO 2005/063214 | July 2005 | WO |
WO 2005/065646 | July 2005 | WO |
WO 2005/066183 | July 2005 | WO |
WO 2005/079760 | September 2005 | WO |
WO 2005/102286 | November 2005 | WO |
WO 2005/102294 | November 2005 | WO |
WO 2005/102294 | November 2005 | WO |
WO 2005/105036 | November 2005 | WO |
WO 2006/002883 | January 2006 | WO |
WO 2006/002884 | January 2006 | WO |
WO 2006/002886 | January 2006 | WO |
WO 2006/002884 | March 2006 | WO |
WO 2006/039692 | April 2006 | WO |
WO 2006/058249 | June 2006 | WO |
WO 2006/082097 | August 2006 | WO |
WO 2006/082099 | August 2006 | WO |
WO 2006/105615 | October 2006 | WO |
WO 2006/128471 | December 2006 | WO |
WO 2007/005716 | January 2007 | WO |
WO 2007/008752 | January 2007 | WO |
WO 2007/014061 | February 2007 | WO |
WO 2007/048233 | May 2007 | WO |
WO 2007/053698 | May 2007 | WO |
WO 2007/085024 | July 2007 | WO |
WO 2007/085024 | July 2007 | WO |
WO 2007/103105 | September 2007 | WO |
WO 2007/103286 | September 2007 | WO |
WO 2007/112273 | October 2007 | WO |
WO 2007/112285 | October 2007 | WO |
WO 2007/112286 | October 2007 | WO |
WO 2007/131357 | November 2007 | WO |
WO 2008/023261 | February 2008 | WO |
WO 2008/033523 | March 2008 | WO |
WO 2008/069941 | June 2008 | WO |
WO 2008/086804 | July 2008 | WO |
WO 2008/107149 | September 2008 | WO |
WO 2008/107149 | September 2008 | WO |
WO 2008/109462 | September 2008 | WO |
WO 2008/132707 | November 2008 | WO |
WO 2008/142627 | November 2008 | WO |
WO 2008/148798 | December 2008 | WO |
WO 2009/005803 | January 2009 | WO |
WO 2009/014534 | January 2009 | WO |
WO 2009/034541 | March 2009 | WO |
WO 2009/034541 | March 2009 | WO |
WO 2009/034541 | March 2009 | WO |
WO 2009/035474 | March 2009 | WO |
WO 2009/051819 | April 2009 | WO |
WO 2009/076764 | June 2009 | WO |
WO 2009/092601 | July 2009 | WO |
WO 2009/110005 | September 2009 | WO |
WO 2009/112273 | September 2009 | WO |
WO 2009/135680 | November 2009 | WO |
WO 2010/022193 | February 2010 | WO |
WO 2010/044842 | April 2010 | WO |
WO 2010/057036 | May 2010 | WO |
WO 2010/066034 | June 2010 | WO |
WO 2010/069050 | June 2010 | WO |
WO 2010/083843 | July 2010 | WO |
WO 2010/083894 | July 2010 | WO |
WO 2010/088911 | August 2010 | WO |
WO 2010/105672 | September 2010 | WO |
WO 2010/140007 | December 2010 | WO |
WO 2010/140007 | December 2010 | WO |
WO 2010/149169 | December 2010 | WO |
WO 2011/008298 | January 2011 | WO |
WO 2011/009602 | January 2011 | WO |
WO 2011/009603 | January 2011 | WO |
WO 2011/009604 | January 2011 | WO |
WO 2011/095314 | August 2011 | WO |
WO 2011/095314 | August 2011 | WO |
WO 2011/128630 | October 2011 | WO |
WO 2011/154414 | December 2011 | WO |
WO 2012/028317 | March 2012 | WO |
WO 2012/028318 | March 2012 | WO |
WO 2012/028319 | March 2012 | WO |
WO 2012/061779 | May 2012 | WO |
WO 2012/076907 | June 2012 | WO |
WO 2012/085657 | June 2012 | WO |
WO 2012/119727 | September 2012 | WO |
WO 2012/166474 | December 2012 | WO |
WO 2013/003845 | January 2013 | WO |
WO 2013/017234 | February 2013 | WO |
WO 2013/017242 | February 2013 | WO |
WO 2013/030177 | March 2013 | WO |
WO 2013/050539 | April 2013 | WO |
WO 2013/072395 | May 2013 | WO |
WO 2013/084059 | June 2013 | WO |
WO 2013/127830 | September 2013 | WO |
WO 2013/127831 | September 2013 | WO |
WO 2013/128276 | September 2013 | WO |
WO 2013/156453 | October 2013 | WO |
WO 2013/167735 | November 2013 | WO |
WO 2014/059512 | April 2014 | WO |
WO 2014/190440 | December 2014 | WO |
WO 2014/191396 | December 2014 | WO |
WO 2014/191397 | December 2014 | WO |
WO 2015/004245 | January 2015 | WO |
WO 2015/103379 | July 2015 | WO |
- Extended European Search Report for Application No. EP 16183922.0-1460, dated Oct. 31, 2016.
- Meyer et al., “Awareness Topic: Mitigating the Risks of Ethanol Induced Dose Dumping from Oral Sustained/Controlled Release Dosage Forms,” FDA ACPS Meeting, Oct. 2005, p. 1-4.
- Baxter, J.L. et al., “Hydrodynamics-induced variability in the USP apparatus II dissolution test,” International Journal of Pharmaceutics 292 (2005) 17-28.
- Bellmann et al., “Development of an advanced in vitro model of the stomach and its evaluation versus human gastric psychology.” Food Research International 88 (2016) 191-198.
- Koziolek, M. et al., “Development of a bio-relevant dissolution test device simulating mechanical aspects present in the fed stomach,” European Journal of Pharmaceutical Sciences 57 (2014) 250-256.
- Remington, Chapter 45, pp. 996-1035. (Full Translation Attached).
- USP Expert Council, US Pharmacopoeia, Chapter 1092, 2007, 1-15.
- Alekseeva et al, Chemical-Pharmaceutical Journal, vol. 41, No. 9, 2007, 49-52. (Full translation attached.).
- Efentakis et al, Effects of Excipients on Swelling and Drug Release from Compressed Matrices, in Drug Development and Industrial Pharmacy 23(1):107-112, Jan. 1997, Abstract.
- Extended European Search Report and Opinion for Application No. EP 15184634.2-1455, dated Mar. 3, 2016.
- Linz et al. “Cebranopadol: A Novel Potent Analgesic Nociception/Orphanin FQ Peptide and Opioid Receptor Agonist,” J Pharmacol. Exp. Ther. 2014; 349: 535-548; available online Apr. 8, 2014.
- Saleem et al. “Formulation and Evaluation of Tramadol hydrochloride Rectal Suppositories,” Indian J. Pharm Sci. Sep.-Oct. 2008; 70(5), 640-644.
- Tennant, “Simultaneous Use of Stimulants and Opioids,” 2011 [online] retrieved on Jul. 7, 2016 from: http://www.practicalpainmanagement.com/treatments/pharmacological/opioids/simultaneous-use-stimulants-opioids; 7 pages.
- The Merck Index, 14th Ed. (2006) No. 0006360 Nalefene.
- The Merck Index, 14th Ed. (2006) No. 0006362 Naloxone.
- The Merck Index, 14th Ed. (2006) No. 0006363 Naltrexone.
- The Merck Index, 14th Ed. (2006) No. 0006959 Oxycodone.
- 2.9 Methoden der pharmazeutischen Technologie, European Pharmacopeia, 143-144, 1997. (Full English translation attached).
- Albertini, B. “New spray congealing atomizer for the microencapsulation of highly concentrated solid and liquid substances” European Journal of Pharmaceutics and Biopharmaceutics 69 (2008) 348-357.
- Almeida, A. et al., Ethylene vinyl acetate as matrix for oral sustained release dosage forms produced via hot-melt extrusion, European Journal of Pharmaceutics and Biopharmaceutics 77 (2011) 297-305.
- Almeida, A. et al., Sustained release from hot-melt extruded matrices based on ethylene vinyl acetate and polyethylene oxide, European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 526-533.
- Andre et al., “O-Demethylation of Opiod Derivatives With Methane Sulfonic Acid/Methoinine: Application to the Synthesis of Naloxone and Analogues” Synthetic Comm. 22(16), pp. 2313-2327, 1992.
- Apicella A.et al., Biomaterials, vol. 14, No. 2, pp. 83-90,1993.
- Application of a modelling system in the formulation of extended release hydrophilic matrices, Reprinted from Pharmaceutical Technology Europe, Jul. 2006.
- Application of Opadry II, complete film coating system, on metformin HCl extended release matrices containing Polyox water soluble resin, Colorcon Apr. 2009.
- Arnold C., “Teen Abuse of Painkiller OxyContin on the Rise,” www.npr.org, Dec. 19, 2005.
- Augustine, R.L., Catalytic Hydrogenation of a, B-Unsaturated Ketones. III The Effect of Quantity and Type of Catalysts, J.Org Chem. 28(1), pp. 152-155, Abstract 1963.
- Avis, Kenneth, Parenteral Preparations. Chapter 85. pp. 1518-1541In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- Bailey, F.E., et al., “Some properties of poly(ethylene oxide) in aqueous solution,” Journal of Applied Polymer Science, vol. 1, Issue No. 1, pp. 56-62, 1959.
- Bauer et al. Lehrbuch der Pharmazeutischen Technologie. Eight Edition 2006. Stuttgart, pp. 343-352.
- Bauer et al. Lehrbuch der Pharmazeutischen Technologie. Sixth Edition 1999. Stuttgart, pp. IX-XV, Table of contents. (Full English translation attached).
- Bauer, Kurt H., et al., Coated Pharmaceutical Dosage Forms—Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials, 1st edition, 1998, CRC Press, Medpharm Scientific Publishers. (Preface, Table of Content, List of Abbreviations, Explanation of Terms only).
- Baum et al.,“The impact of the addition of naloxone on the use and abuse of pentazocine”, Public Health Reports, Jul.-Aug. 1987, vol. 102, No. 4, p. 426-429.
- Bingwen et al, 2008, p. 367. (full translation attached).
- Block, Lawrence. Medicated Applications. Chapter 88. In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- Borquist et al., “Simulation of the release from a multiparticulate system validated by single pellet and dose release experiements,” J. Controlled Release, 97: 453-465 (2004).
- Braun, et al. A study of Bite Force. Part 2: Relationship to Various cephalometric Measurements. Angel Orthodontist, vol. 65 (5) pp. 373-377, 1995.
- Brown, The Dissolution Procedure: Development and Validation, heading “Study Design”, “Time Points” US Pharmacopoeia (USP), vol. 31(5), General Chapter 1092, pp. 1-15, 2006.
- Bruce et al, Properties of hot-melt extuded tablet formulations for the colonic delivery of 5-aminosalicylic acid, European Journal of Pharmaceutics and Biopharmaceutics, 59 (2005) 85-97.
- Caraballo, Journal of Controlled Release, vol. 69, pp. 345-355, 2000.
- Carbopol 71G, retrieved Mar. 10, 2014 from http://www.lubrizol.com/LifeScience/Products/Carbopol71G-NF.html.
- Cawello, “Parameters for Compartment-free Pharmacokinetics—Standardization of Study Design, Data Analysis and Reporting” 1999, pp. XI-XIII (table of contents).
- Chibuzor et al. “Formulation Development and Evaluation of Drug Release Kinetics from Colon-Targeted Ibuprofen Tablets Based on Eudragit RL 100-Chitosan Interpolyelectrolyte Complexes,” Hindawi Publ. Corporation ISRN Pharmaceutics, vol. 2013, Article ID 838403.
- Committee for Proprietary Medicinal Products. Note for Guidance on the Investigation of Bioavailability and Bioequivalence. 2001. pp. 1-18.
- Coppens et al., “Hypromellose, Ethylcellulose, and Polyethylene Oxide Use in Hot Melt Extrusion”; Pharmaceutical Technology, 62-70, Jan. 2005.
- Cornish, P. “Avoid the Crush”: hazards of medication administration in patients with dysphagia or a feeding tube, CMA Media Inc., CMAJ. 172(7), pp. 871-872, 2005.
- Costa et al. “Modeling and comparison of dissolution profiles”; European Journal of Pharmaceutical Sciences 13 (2001) 123-33.
- Crowley M.M. et al., “Stability of polyethylene oxide in matrix tablets prepared by hot-melt extrusion,” Biomaterials 23, 2002, pp. 4241-4248.
- Crowley MM, Drug Dev Ind Pharm. Sep. 2007; 33(9):909-26. (Abstract only).
- Cuesov, Drug Production Technology, Khar'kov, 1999, pp. 351-352.
- Dachille et al., “High-pressure Phase Transformations in Laboratory Mechanical Mixers and Mortars”, Nature, vol. 186, Apr. 2, 1960, pp. 34 and 71.
- Dachille, F. et al., “High-Pressure Phase Transformation in Laboratory Mechanical Mixers and Mortars”, 1960., Nature, vol. 186, pp. 1-2 (abstract).
- Davies, et al; European Journal of Pharmaceutics and Biopharmaceutics, 67, 2007, pp. 268-276.
- Dean, D.A., E.R. Evans, I.H. Hall, Pharmaceutical Packaging Technology, Taylor & Francis, 1st Edition, Nov. 30, 2000 (Publisher description dated Oct. 22, 2010).
- Deighan, C.J. et al., Rhabdomyolysis and acute renal failure resulting from alcohol and drug abuse, Q.J. Med, vol. 93, 2000, pp. 29-33.
- Dejong (Pharmaceutisch Weekblad Scientific Edition) 1987, p. 24-28.
- Dexheimer, Terahertz Spectroscopy: Principles and Applications (Optical Science and Engineering Series), CRC; 1 edition 2007. (Table of content only).
- Dierickx et al., “Co-extrusion as manufacturing technique for fixed-dose combination mini-matrices,” European Journal of Pharmaceutics and Biopharmaceutics 81 (2012), 683-689.
- Disanto, Anthony. Bioavailability and Bioequivalency Testing. Chapter 77. In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- Dow Chemical Company, “Using Dow Excipients for Controlled Release of Drugs in Hydrophilic Matrix Systems”, Sep. 2006, pp. 1-36.
- Dow Excipients Chem. of Poly. Water Soluble-Resin 2004, pp. 1-2.
- Dow Technical Data, Polyox WSR Solid Dosage Formulation via Melt Extrusion, Feb. 2003, pp. 1-3.
- Efentakis M et al. “Evaluation of High Molecular Weight Poly(Oxyethylene) (Polyox) Polymer: Studies of Flow Properties and Release Rates of Furosemide and Captopril from controlled-Release hard Gelatin Capsules”, Pharmaceutical Development and Technology, 5 (3), pp. 339-346, 2000.
- Eggleston, “The seat of the emetic action of various drugs,” J. Pharmacol. Exp. Ther. 7, 225-253 (1915).
- El-Egakey, Adel et al, “Hot extruded dosage forms Part I Technology and dissolution kinetics of polymeric matrices” Pharmacerutica Acta Helvetiae, vol. 46, pp. 31-53,Mar. 19, 1970.
- El-Sherbiny I.M. et al “Preparation, characterization, swelling and in vitro drug release behaviour of poly[N-acryloylglycine-chitosan] interplymeric pH and thermally-resposive hydrogels”, European Polymer Journal, vol. 41, pp. 2584-2591, 2005.
- Encyclopedia of Pharmaceutical Technology, Third Edition, vol. 1, edited by James Swarbrick PharmaceuTech, Inc., Pinehurst, North Carolinia, USA (Table of Contents only), Oct. 25, 2006.
- Encyclopedia of Pharmaceutical Technology, Third Edition, vol. 2, edited by James Swarbrick PharmaceuTech, Inc., Pinehurst, North Carolinia, USA (Table of Contents only), Oct. 25, 2006.
- Encyclopedia of Pharmaceutical Technology, Third Edition, vol. 3 edited by James Swarbrick PharmaceuTech, Inc., Pinehurst, North Carolinia, USA (Table of Contents only), Oct. 25, 2006.
- Encyclopedia of Pharmaceutical Technology, Third Edition, vol. 4, edited by James Swarbrick PharmaceuTech, Inc., Pinehurst, North Carolinia, USA (Table of Contents only), Oct. 25, 2006.
- Encyclopedia of Pharmaceutical Technology, Third Edition, vol. 5, edited by James Swarbrick PharmaceuTech, Inc., Pinehurst, North Carolinia, USA (Table of Contents only), Oct. 25, 2006.
- Encyclopedia of Pharmaceutical Technology, Third Edition, vol. 6, edited by James Swarbrick PharmaceuTech, Inc., Pinehurst, North Carolinia, USA (Table of Contents only), Oct. 25, 2006.
- Encyclopedia of Pharmacological Technology, Informa Healthcare, 1st Ed., 1996, vol. 14 (Table of Content only).
- Erskine, Jr., Clyde. Quality Assurance and Control. Chapter 83. pp. 1487-1491 In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- Eudragit NE40D web page from Evonik website; downloaded Feb. 24, 2015.
- Eudragit RS PO web page from Evonik website; downloaded Feb. 24, 2015.
- European Pharmacopeia 5.0; Glyceryl behenate monograph; dated Jan. 2005; downloaded Feb. 24, 2015.
- European Pharmacopoeia 2.9.40 “Uniformity of Dosage Units”, 2006, pp. 3370-3373.
- European Pharmacopoeia 5.0, 2.9.8 “Resistance to Crushing of Tablets”, 2005, p. 235.
- European Pharmacopoeia, Third Edition Supplement 2000, Council of Europe, Strasbourg, 2000, pp. 85-107.
- European Pharmacopoeia, Third Edition, Council of Europe, Strasbourg, 1997, pp. 127-152.
- European Search Report and Opinion Application No. 12002708.1-1219, dated Sep. 24, 2012.
- European Search Report and Opinion Application No. 14176277.3-1460, dated Dec. 15, 2014.
- European Search Report and Opinion, Application No. 11006253.6-2112, dated Dec. 16, 2011.
- European Search Report and Opinion, Application No. 11006254.4-2112, dated Dec. 16, 2011.
- European Search Report and Opinion, Application No. 11008131.2-1219, dated Feb. 24, 2012.
- European Search Report and Opinion, Application No. 11009129.5-2112, dated Apr. 10, 2012.
- European Search Report and Opinion, Application No. 12001296.8-1219, dated Jun. 26, 2012.
- European Search Report and Opinion, Application No. 12001301.6-1219, dated Jun. 26, 2012.
- European Search Report and Opinion, Application No. 12003743.7-1219, dated Sep. 24, 2012.
- European Search Report and Written Opinion for EP Application No. 13169658.5, dated Aug. 6, 2013.
- European Search Report and Written Opinion for EP Application No. 13169659.3, dated Aug. 6, 2013.
- European Search Report and Written Opinion for EP Application No. 13176309.9-1460, dated Oct. 9, 2013.
- European Search Report and Written Opinion for EP Application No. 13197503.9-1460, dated Feb. 18, 2014.
- European Search Report and Written Opinion for EP Application No. 13425151.1-1460, dated Mar. 11, 2014.
- European Search Report and Written Opinion for EP Application No. 14169801.9-1455 dated Oct. 20, 2014.
- Evaluation of Verapamil HCl (240 mg) Extended Release Matrix Formulation Using USP Apparatus III in Biorelevant Dissolution Media, Jul. 2009.
- Evonik Industries, Eudragit Application Guidelines, 10th Edition, 2008, (Table of Contents only).
- Evonik Rohm GmbH product brochure: Eudragit acrylic polymers for solid oral dosage forms (2009).
- Extended European Search Report and Opinion for Application No. EP 15153679.4-1455, dated Jun. 30, 2015.
- Extended European Search Report and Opinion for Application No. EP 15165064.5-1455, dated Oct. 16, 2015.
- Extended European Search Report and Opinion for Application No. EP 15165065.2-1455, dated Nov. 2, 2015.
- Extended European Search Report and Opinion for Application No. EP 15165067.8-1455, dated Nov. 2, 2015.
- Extended European Search Report and Opinion for Application No. EP 15165069.4-1455, dated Nov. 2, 2015.
- Extended European Search Report and Opinion for Application No. EP 15165070.2-1455, dated Nov. 2, 2015.
- Fell J.T., et al, “Determinination of Tablet Strength by the Diametral-Compression Test” Journal of Pharmaceutical Sciences, vol. 59, No. 5, May 1970, pp. 688-691.
- Follonier N. et al., “Evaluation of hot-melt extrusion as a new technique for the production of polymer-based pellets for sustained release capsules containing high loadings of freely soluble drugs,” Drug Development and Industrial Pharmacy, 20(8), pp. 1323-1339, 1994.
- Follonier, N. et al., “Various ways of modulating the release of dltiazem hydrochloride from hot-melt extruded sustained release pellets prepared using polymeric materials” Journal of Controlled Release 36, pp. 243-250, 1995.
- Formulation of Polyox ER Matrices for a Highly Soluble Active, Colorcon Jul. 2009.
- Foye, W., Principles of Medicinal Chemistry; Analgesics pp. 241-242, at 241 (1989).
- Foye, W., Principles of Medicinal Chemistry; Structural Features and Pharmacologic Activity, pp. 63-66 at 65 (1989).
- Freed et al., “pH Control of Nucleophilic/electrophilic oxidation”, International Journal of Pharmaceutics, vol. 357, pp. 180-188 (2008).
- Giles R. et al. Plastic Packaging Materials. Chapter 81. pp. 1473-1477 In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- Goodman and Gilman, “The Pharmacological Basis of Therapeutics, Seventh Edition”, MacMillan Publishing Company, Table of Contents. 1985.
- Goodman and Gilman, 1985, 7th edition, chapter 22, 491-530.
- Goodman and Gilman, 1985, 7th edition, chapter 23, 533-579.
- Graham N.B., Poly(Ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, p. 263-291 Chapter 17, 1992.
- Griffin W, “Classification of Surface-Active Agents by HLB” Journal of the Society of Cosmetic Chemists, Atlas Powder Company, 1949, pp. 311-326.
- Griffith, et al. “Tablet Crushing and the Law: The Implications for Nursing” Professional Nurse 19(1), pp. 41-42, 2003.
- Gryczke et al, “Development and evaluation of orally disintegrating tablets (ODTs) containing Ibuprofen granules prepared by hot melt extrusion”, Colloids and surfaces., B, Biointerfaces, Elsevier, Amsteram, NL, vol. 86, No. 2, Apr. 5, 2011, pp. 275-284.
- Guidance for Industry—Bioavailability and Bioequivalence—Studies for Orally Administered Drug Products—General Considerations, FDA, BP, Announced in the Federal Register: vol. 68, No. 53/Mar. 19, 2003.
- Guidance for Industry—Statistical Approaches to Establishing Bioequivalence, FDA, BP, Jan. 2001.
- Handbook of Pharmaceutical Excipients, 1986, American Pharmaceutical Association, Washington, DC and London (Table of Content Only).
- Handbuch der Kunststoff-Extrusionstechnik 1, “Grundlagen” in Chapter 1.2 “Klassifizierung von Extrudern”, pp. 3-7. 1989. (Full english translation attached).
- Hanning C.D.et al. “The Morphone Hydrogel Suppository. A New Sustained release Rectal Preparation”, British Journal of Anaesthesia, 61, pp. 221-227, 1988.
- Hartauer, Kerry J. “Influence of Peroxide Impurities in Povidone and Crospovidone on the Stability of Raloxife” Pharma. Dev. & Tech, 5 (3) 303-310 (2000).
- Henriest D. et al. In vitro and in vivo evaluation of starch-based hot stage extruded double matrix systems. Journal of Controlled Release. 2001, vol. 75, pp. 391-400.
- Hoepfner et al. Fiedler Encyclopedia of Excipients. Sixth Edition, 2007, Aulendorf, Germany; Table of Contents only.
- Hong S. et al. Dissolution kinetics and physical characterization of three-layered tablet with poly(ethylene oxide) core matrix capped by Carbopol. Int .J. Pharmacol. 2008, vol. 356, pp. 121-129.
- Inert gas—Wikipedia, Dec. 2009, pp. 1-3.
- Investigation of a Directly Compressible Metformin HCl 500mg Extended Release Formulation Based on Hypromellose, Colorcon Jul. 2009.
- James, A. “The legal and clinical implications of crushing tablet medication”, Nurse Times 100(50), 28-33, 2004.
- Janicki S. et al. “Slow-Release Microballs: Method of Preparation”, Acta Pharm. Technol. 33 (3) 154-155, 1987.
- Jannetto, P. et al, “Oxycodone: Recognition and Pharmacogenomics,” Toxicology News, Mar. 2003, 1-7.
- Kalant H. et al., Death in Amphetamine Users: Caues and Rates, CMA Journal, vol. 112 (Feb. 8, 1975): 299-304.
- Katz N. et al. “Challenges in the development of prescription opioid abuse-deterrent formulations”, Clin. J. Pain, 23(8): 648-660 (Oct. 2007).
- Kim C.-J. “Drug Release from Compressed Hydrophilic Polyox-WSR Tablets” J Pharm. Sciences 1995, 84(3): pp. 303-306.
- Kim N et al. “Preparation and Evaluation of Eudragit Gels. V. Rectal Gel Preparations for Sustained Release and Avoidance of First-Pass Metabolism of Lidocaine”, Chem. Pharm Bull. 1992, 40(10), 2800-2804.
- King et al. Oral Solid Dosage Forms. Chapter 90. pp. 163-1632 In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- King, R, “Tablets, Capsules, and Pills” Remington's Pharmaceutical Sciences, pp. 1553-1593, Ch. 89, 1980, 16th Edition.
- King, Remington's Pharmaceutical Sciences 17th ed., Chapter 78, p. 1418 (1985).
- Knevel, Adelbert. Separation. Chapter 78. pp. 1432-1442 In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- Kolter, K., “Compression Behaviour of Kollidon SR,” APV/ APGI 2002, Florence, Apr. 11, 2002.
- Kondrat, T. , “Technology dosage forms” Moscow 1991, p. 96.
- Lee, Y.-S. et al., Principles of Terahertz Science and Technology (Lecture Notes in Physics), Springer; 1 edition 2008. (Table of Contents Only).
- Lenindzer, A., “The molecular basis of the structure and functions of cells” Moscow 1974, p. 68.
- Levina et al., “The Effect of Ultrasonic Vibration on the Compaction Characteristics of Ibuprofen” Drug Development and Industrial Pharmacy, vol. 28, No. 5, pp. 495-514, 2002.
- Levina M. et al “The Effect of Ultrasonic Vibration on the Compaction Characteristics of Paracetamol”, Journal of Pharmaceutical Sciences, vol. 89, No. 6, pp. 705-723, Jun. 2000.
- Li et al, “Characterization of Poly(Ethylene Oxide) as a Drug Carrier in Hot-Melt Extrusion”, Drug Development and Industrial Pharmacy, vol. 32, No. 8, Jan. 1, 2006, pp. 991-1002.
- Lieberman, Herbert A., Pharmaceutical Dosage Forms, Tablets, Second Edition, Revised and Expanded, 1990. vol. 2 (Cover and Table of Content only).
- Lintner, Carl. Stability of Pharmaceutical Products. Chapter 82. pp. 1478-1486 In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- Liu J. et al., “Properties of Lipophilic Matrix Tables Containing Phenylpropanolamine Hydrochloride Prepared by Hot-Melt Extrusion”, EJPB, 52 (2001), pp. 181-190.
- Lockhart H. et al, “Packaging of Pharnaceuticals and Health Care Products”; Blackie Academic & Professional; First Edition 1996. (Table of contents only).
- Longer et al. Sustained-Release Drug Delivery Systems. Chapter 92. pp. 1611-1661 In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- Madorsky S.L. “Thermal degradation of Polyethylene Oxide and Polypropylene Oxide”, Journal of Polymer Science, pp. 183-194 vol. 36, No. 3, Mar. 1959.
- Maggi et al., “Dissolution behavior of hydrophilic matrix tablets containing two different polyethylene oxides (PEOs) for the controlled release of a water-soluble drug. Dimensionality study” Biomaterials, 2002, 23, 1113-1119.
- Maggi L.et al, “High molecular weight polyethylene oxides (PEOs) as an alternative to HPMC in controlled release dosage form”, 2000, International Journal of Pharmaceutics, 195 pp. 229-238.
- Maggi, C.. Therapeutic Potential of Capsaicin-like Molecules. Life Sciences, vol. 51, pp. 1777-1781, 1992.
- Mank R. et al., “Darstellung wirkstoffhaltiger Extrusionsformlinge auf der Basis von Thermoplasten. Teil 1: Untersuchung zur Wirkstoffliberation” Pharmazie 44, H. 11, pp. 773-776, 1989. English language translation of relevant paragraph provided.
- Mank R., “Darstellung wirkstoffhaltiger Extrusionsformlinge auf der Basis von Thermoplasten. Teil 2: Unersuchungen zur Optimierung der Wirkstofffreigabe” Pharmazie 45, H. 8, pp. 592-593 1990. English language translation of relevant paragraph provided.
- Marques, Tablet breaking force, 2008.
- Matos, Dr. Rick, Ph.D—Letter Jan. 6, 2011.
- McGary, C.W.. Jr. “Degradation of Poly(ethylene Oxide)”, Journal of Polymer Science vol. XLVI,1960, pp. 51-57.
- McGinity et al., Hot-Melt Extrusion as a Pharmaceutical Process, American Pharmaceutical Review, vol. 4 (2), pp. 25-36, 2001.
- McGinity, J.W.—Letter of Jan. 26, 2009, pp. 1-4.
- McNeill M. et al. Properties controlling the diffusion and release of water-soluble solutes from poly(ethylene oxide) hydrogels. 4. Extended constant rate release from partly-coated spheres. Journal Biomat. Sci. Polymer. Ed. 1996, vol. 7, pp. 953-963.
- Mesiha M.S. et al “A Screening Study of Lubricants in Wet Powder Passes Suitable for extrusio-spheronization”, Drug Development and Industrial Pharmacy, 19(8), pp. 943-959, 1993.
- Metformin Hydrochloride 1000 mg Extended Release Tablets, Lubrizol Advanced Materials, Inc., Nov. 20, 2009, Previous Edition Dec. 19, 2008.
- Metformin Hydrochloride 750 mg Extended Release Tablets, Lubrizol Advanced Materials, Inc., Sep. 2010.
- Miles, R.E. et al., Terahertz Frequency Detection and Identification of Materials and Objects (NATO Science for Peace and Security Series B: Physics and Biophysics), Springer; 1 edition 2007. (Table of contents).
- Miller “To crush or not to crush? What to consider before giving medications to a patent with a tube or who has trouble swallowing”, Nursing, pp. 50-52, Feb. 2000.
- Mises à jour cumulatives, Vidal, Jan./Oct. 2002 (full translation attached).
- Mitchell, “Oral Dosage Forms That Should Not Be Crushed: 2000 Update” Hospital Pharmacy 35(5), 553-557, 2000.
- Monolithic: retrieved from internet: http:/merriam-webster.com/dictionary/monolithic. Retrieved on Sep. 2, 2015.
- Moorman-Li, R. et al, “A Review of Abuse-Deterrent Opioids for Chronic Nonmalignant Pain.” Pharmacy and Therapeutics, vol. 37 No. 7, Jul. 2012, pp. 412-421.
- Morissette et al. Advanced Drug Delivery Review 26 (2004), 275-300.
- Moroni A. et al, “Application of Poly(Oxyethylene) Homopolymers in Sustained release Solid formulations” Drug Development and Industrial Pharmacy, 21(12) pp. 1411-1428, 1995.
- Mullins, John. Ophthalmic Preparations. Chapter 87. pp. 1553-1563; In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- Munjal M. et al., “Polymeric Systems for Amorphous Delta9-Tetrahydrocannabinol Produced by a Hot-Melt Method. Part II: Effect of Oxidation Mechanisms and Chemical Interactions on Stability” Journal of Pharmaceutical Sciences vol. 95 No. 11, Wiley InterScience, 2006, pp. 2473-2485.
- Munsell Color Company, “The Munsell Book of Color: Glossy Collection”, X-Rite, Originally published in 1966, pp. 1-7.
- Nairn, J.G., Solutions, Emulsion, Suspensions and Extractives. Chapter 84. pp. 1492-1517, In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- Note for Guidance on Stability Testing, EMEA, Aug. 2003, pp. 1-20.
- Note for Guidance on the Investigation of Bioavailability and Bioequivalence, EMEA, London, Jul. 26, 2001 (CPMP/EWP/QWP/1401/98).
- Ohnishi N. et al., Effect of the Molecular Weight of Polyethylene Glycol on the Bioavailability of Indomethacin Sustained-Release suppoositories Prepared with Solid Dispersion, Chem. Pharm. Bull, 35(8), pp. 3511-3515, 1987.
- Oliveira et al., “Production and characterization of laminar coextrudates at room temperature in the absence of solvents,” AAPS Annual Meeting and Exposition, Oct. 14-18, 2012, Chicago, USA.
- Oxicotin: Balancing Risks and Benefits, United States Senate, Hearing, Feb. 12, 2002.
- Oxycodon (Oxygesic): Missbrauch, Abhaengigkeit und toedliche Folgen durch Injection zerstossener Retardtabletten, Deutsches Ärzteblatt, vol. 36, A2326-A2326, Sep. 5, 2003.
- Ozeki T. et al. “Control of Medicine Release From Solid Dispersion Through Poly(ethylene oxide)-Carboxyvinylpolymer Interaction”, International Journal of Pharmaceutics, 165, 1998, pp. 239-244.
- Ozeki T. et al. “Controlled Release From Solid Dispersion Composed of Poly(ethylene oxide)-Carbopol Interpolymer Complex With Various Cross-Linking Degrees of Carbopol”, Journal of Controlled Release. 63, 2000. pp. 287-295.
- Ozeki T. et al., “Control of medicine release from solid dispersion composed of the poly(ethylene oxide)-carboxyviylpolymer interpolymer complex by varying molecular wight of poly(ethylene oxide)” Journal of Controlled Release 58, pp. 87-95, 1999.
- PCT International Search Report and Written Opinion for PCT Application No. PCT/EP2010/004459 dated Dec. 1, 2010.
- PCT International Search Report and Written Opinion for PCT Application No. PCT/EP2009/003290 dated Jul. 9, 2009.
- PCT International Search Report and Written Opinion for PCT Application No. PCT/EP2013/053894 dated Mar. 22, 2013.
- PCT International Search Report and Written Opinion for PCT Application No. PCT/EP2013/057851 dated Jun. 12, 2013.
- PCT International Search Report and Written Opinion for PCT Application No. PCT/EP2013/059728 dated Aug. 6, 2013.
- PCT International Search Report and Written Opinion for PCT Application No. PCT/EP2014/064830 dated Aug. 6, 2014.
- PCT International Search Report and Written Opinion for PCT Application No. PCT/EP2014/075618 dated Feb. 11, 2015.
- PCT International Search Report and Written Opinion for PCT Application No. PCT/EP2014/0777748 dated Feb. 12, 2015.
- PCT International Search Report and Written Opinion for PCT Application No. PCT/EP2015/060377 dated Jul. 23, 2015.
- PCT International Search Report and Written Opinion for PCT Application No. PCT/EP2015/061343 dated Jul. 21, 2015.
- PCT Second Written Opinion for PCT Application No. PCT/EP2013/053893 dated Feb. 21, 2014.
- PCT Second Written Opinion for PCT Application No. PCT/EP2013/057851 dated Apr. 15, 2014.
- Pentoxifylline 400 mg Extended Release Tablets, Lubrizol Advanced Materials, Inc., Mar. 3, 2011, Previous Edition Nov. 19, 2009.
- Perez-Marcos, B., Usefulness of certain varieties of Carbomer in the formulation of hydrophilic furosemide matrices, International Journal of Pharmaceutics, 67 (1991) 113-121.
- Pharm. Research, Official Journal of the American Association of Pharmaceutical Scientists, Sep. 1989, 6(9), S-98.
- Pharm. Research, Official Journal of the American Association of Pharmaceutical Scientists, Oct. 1991, 8(10), S-192.
- Phillips, G. Briggs. Sterilization. Chapter 79. pp. 1443-1454, In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- Physico-mechanical Characterization of Polyox for Table Manufacture, Colorcon Jul. 2009.
- Pillay V. et al. A novel approach for constant rate delivery of highly soluble bioactives from a simple monolithic system. Journal of Controlled Release. 2000, vol. 67, pp. 67-78.
- Pinto, Joao F. et al.,“Evaluation of the Potential Use of Poly(ethylene oxide) as Tablet- and Extrudate-Forming Material,” AAPS PharmSci, 2004; 6 (2), Article 15, pp. 1-10, (http://www.aapspharmsci.org).
- Piringer, O.G.and A.L. Baner, Plastic Packaging: Interactions with Food and Pharmaceuticals, Wiley VCH, 2nd Completely Revised Edition, Feb. 13, 2008. (Table of Contents only).
- Polyox water soluble resins 2003. http://www.dow.com/webapps/lit/litorder.asp?filepath=polyox/pdfs/noreg/326-00002.pdf.
- Polyox water-soluble resins (Dow Mar. 2002); see http://msdssearch.dow.com/PublishedLiteratureDOWCOM/dh_0031/0901b80380031a4a.pdf?filepath=/326-00001.pdf&fromPage=GetDoc).
- Polyox WSR-303, retrieved Mar. 10, 2014 from URL http://www.dow.com/dowwolff/en/industrial_solutions/polymers/polyethylene.
- Polyox, Colorcon, Application Data (Apr. 2009) downloaded from http://www.colorcon.com/literature/marketing/mr/Extended%20Release/POLYOX/English/ads_PEO_Antioxidant.pdf.
- Pontier, C. et al, “Use of cycles of compression to characterize the behavior of apatitic phosphate powders,” Journal of the European Ceramic Society 22 (2002), 1205-1216.
- Porter, S. Coating of Pharmaceutical Dosage Forms. Chapter 91. pp. 1633-1643 In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- Prapaitrakul W. et al, “Release of Chlorpheniramine Maleate from Fatty Acid Ester Matrix disks Prepared by Melt-extrusion” J. Pharm. Pharmacol. 43, pp. 377-381, 1991.
- Proeschel, P.A. et al., “Task-dependence of activity / bite-force Relations and its impact on estimation of chewing force from EMG”; J. Dent. Res., vol. 81, No. 7, pp. 464-468, 2002.
- Purdue News, “Purdue Pharma Provides Update on Development of New Abuse-Resistant Pain Medications; FDA Cites Patient Needs as First Priority; New Drug Application Delayed,” www.headaches.about.com, Jun. 18, 2002, pp. 1-6.
- Quintavalle et al., “Preparation of sustained release co-extrudates by hot-melt extrusion and mathematical modelling of in vitro/in vivo drug release profiles,” European Journal of Pharmaceutical Sciences 33 (2008), 282-293.
- Radko S.et al., Applied ad Theoretical Electrophoresis 5, pp. 79-88, 1995.
- Ravin, L. Preformulation. Chapter 76, pp. 1409-1423, In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- Remington, The Science and Practice of Pharmacy, 19th ed., vol. II, p. 1457 (1995) (providing a table of DFA-approved commercially marketed salts).
- Repka M. et al., Bioadhesive Properties of Hydroxypropylcellulose Topical Films Produced by Hot-Melt Extrusion, Journal of Controlled Release, 70 (2001), pp. 341-351.
- Repka Ma, Drug Dev Ind Pharm. Oct. 2007; 33(10):1043. (Abstract).
- Riippi M. et al., The effect of compression force on surface structure, crushing strength, friability and disintegration time of erythromycin acistrate tablets, Eur J Pharm Biopharm, vol. 46, 1998, pp. 339-345.
- Rippie E.G. et al, “Regulation of Dissolution Rate by Pellet Geometry” Journal of Pharmaceutical Sciences, Vo. 58, No. 4, pp. 428-431, Apr. 1969.
- Rippie, E. Powders. Chapter 89, pp. 1585-1602, In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- Ritschel et al. Die Tablette: Handbuch der Entwicklung, Herstellung und Qualitatssicherung. 2nd Edition, 2002, Ch 6, pp. 515-519. (Full English translation attached).
- Ritschel et al. Die Tablette: Handbuch der Entwicklung, Herstellung und Qualitatssicherung. 2nd Edition, 2002, Ch 6, pp. 69-82 and 115-136.
- Ritschel et al. Die Tablette: Handbuch der Entwicklung, Herstellung und Qualitatssicherung. 2nd Edition, 2002, Table of content.
- Rosiaux et al. “Ethanol-resistant ethylcellulose/guar gum coatings—Importance for formulation parameters” European Journal of Pharmaceutics and Bioharmaceutics, vol. 85, N0. 3, (Jul. 25, 2013). pp. 1250-1258.
- Rowe C et al. Handbook of Pharmaceutical Excipients. Sixth Edition. 2009, Edition Cantor Verlag Aulendorf, pp. V-IX, Table of Contents.
- Rowe C et al., Handbook of Pharmaceutical Excipients, 7th Edition, 2012, Table of Contents.
- Salomies et al., “Determination of Oxycodone Hydrochloride in Oral Solutions by High-Performance Thin-Layer Chromatography/Densitometry,” Journal of AOAC International, 83: 1497-1501 (2000).
- Satish et al. “Formulation and Characterization of Matrix and Triple Layer Matrix Tablets for Controlled Delivery of Tramadol Hydrochloride,” International Journal of Pharmaceutical Sciences; 5(4) (2013) 458-464.
- Sax et al., Hawley's Condensed Chemical Dictionary, 11th ed., 1987, p. 1233, definition of “wax”.
- Scheirs J., et al.“Characterizing the Solid-State Thermal Oxidation of Poly (ethylene oxide) Powder”, pp. 2014-2019, Polymer, vol. 32, No. 11, 1991.
- Schier et al. “Fatality from Administration of Labetalol and Crushed Extended-Release Nifedipine” The Annals of Pharmacotherapy vol. 37, 1420-1423, Oct. 2003.
- Schroeder J., et al. Granulierung hydrophober Wirkstoffe im Planetwalzenextruder, Pharm. Ind. 2003, vol. 65, No. 4, 367-372. (Full English translation attached).
- Sciarra et al. Aerosols. Chapter 93., pp. 1662-1677, In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- Search result conducted on http://www.unitconversion.org/force/newtons-to-kiloponds-convresion.html, on Jul. 5, 2011 (Conversion of 18.8 kiloponds to newtons).
- Shivanand P et al., “Factors Affecting Release of KCl From Melt extruded Polyethylene Disks”, Pharmaceutical Research, Oct. 1991, vol. 8, No. 10, p. S-192.
- Sidhu et al., “Watch for nonpsychotropics causing psychiatric side effects,” Current Psychiatry, vol. 7, No. 4, 2008, 61-74.
- Siegel, P. Tonicity, Osmoticity, Osmolality, and Osmolarity. Chapter 80. pp. 1454-1472 In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- Silver, J. “Painkiller OxyContin most commonly abused prescription drug on the streets of Western Pennsylvania”, Pittsburg Post-Gazette, Apr. 8, 2001.
- Spassov et al., Stereochemistry of Diastereomeric 3-Dialkylaminopropanols and O-Derivatives, J.f. prakt. Chemie, 323:5, 793-800 (1981).
- Sprockel O.L et al. “Permeability of Cellulose Polymers: Water Vapour Transmission Rates”., J. Pharma. Pharmacol. 42, pp. 152-157, 1990.
- Sreenivasa, B. et al, Design and Evaluation of Ethylene Vinyl Acetate Sintered Matrix Tablets, Indian Journal of Pharmaceutical Sciences, Sep.-Oct. 2003, 65(5): 496-502.
- Stafford J., Überzogene feste Formen, 1991, 347-68. (English translation attached).
- Strang, Abuse of buprenorphie (Temgesic) by snorting, Letter to the editor, British Med. J., 302: 969 (1991).
- Stringer J.L., et al “Diffusion of small molecular weight drugs in radiation-crosslinked poly(ethylene oxide) hydrogels”, Journal of Controlled Release 42, pp. 195-202, 1996.
- Summers et al; “Influence of Crystal Form on Tensile Strength of Compacts of Pharmaceutical Materials” Journal of Pharmaceutical Sciences, vol. 66, No. 8, Aug. 1977, pp. 1172-1175.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 1, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 10, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 11, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 12, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 13, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 14, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 15, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 16, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 18, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 19, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 2, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 20, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 3, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 4, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 5, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 6, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 7, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 8, table of contents.
- Swarbrick, Encyclopedia of Pharmaceutical Technology, Informa Healthcare, 1988, 1st edition, vol. 9, table of contents.
- Tablet, www.docstoc.com (2011).
- Third Party Observations filed with EPO for Patent EP658055B1, Feb. 2, 2009, pp. 1-8.
- Thoma V.K. et al. “Bestimmung der In-vitro-Freigabe von schwach basischen Wirkstoffen aus Ratardarzneiformen”, pp. 299-301, Pharm. Ind. 51, Nr. 3, 1989.
- Tikhonov, A. et al, Biopharmacy. The Manual for Students of Pharmaceutical Universities and Departments, 2003, pp. 40-41, Kharkov, Ukraine (Full English translation attached).
- Tipler, et al, Physics for Scientists and Engineers, vol. I, 6th Edition, pp. 234-235, 2003.
- Tompkins et al., “Human abuse liability assessment of oxycodone combined with ultra-low-dose natrexone,” Psychopharma., 210: 471-480 (2010).
- Tramadol Hydrochloride 100 mg Extended Release Tablets, Lubrizol Advanced Materials, Inc., Sep. 2010.
- Tranquilan-Aranilla et al., “Kappa-carrageenan-polyethylene oxide hydrogel blends prepared by gamma irradiation,” Radiation Physics and Chemistry vol. 55, pp. 127-131, 1999.
- Turco et al. Intravenous Admixtures. Chapter 86. pp. 1542-1552, In Remington's Pharmaceutical Sciences, 17th Ed, 1985.
- US Pharmacopoeia, Chapter 1217, Aug. 12, 2008.
- Varma et al, Factors Affecting Mechanism and Kinetics of Drug Release from Matrix-Based Oral Controlled Drug Delivery Systems, Am. J. Drug Deliv. 2004: 2 (1): 43-57.
- Verhoeven et al., “Influence of polyethylene glycol/polyethylene oxide on the release characteristics of sustained-release ethylcellulose mini-matrices produced by hot-melt extrusion: in vitro and in vivo evaluations,” European Journal of Pharmaceutics and Biopharmaceutics 72 (2009) 463-470.
- Verhoeven, et al. “Xanthan gum to tailor drug release of sustained-release ethylcellulose mini-matrices prepared via hotmelt extrusion: in vitro and in vivo evaluation,” European Journal of Pharmaceutics and Biopharmaceutics, 63 (2006) 320-330.
- Vippagunta et al. Crystalline Solids, Advanced Drug Delivery Review 48 (2001), 3-26.
- Vynckier et al.,“Hot-melt co-extrusion for the production of fixed-dose combination products with a controlled release ethylcellulose matrix core,” International Journal of Pharmaceutics 464 (2014), 65-74.
- Wade and Weller, “Handbook of Pharmaceutical Excipients: 2nd Edition”, The American Pharmaceutical Association and The Pharmaceutical Press, Washington and London, Table of Contents pp. v-vi, 1994.
- Wagner, Pharmazeutische Biologie—Drogen und ihre Inhaltsstoffe—Scharfstoffdrogen, 2nd., revised edition, Gustav Fischer Verlag, Stuttgart—N.Y., 1982, pp. 82-92 (Full English Translation attached).
- Wagner, Pharmazeutische Biologie—Drogen und ihre Inhaltsstoffe—Scharfstoffdrogen, 2nd., revised edition, Gustav Fischer Verlag, Stuttgart—N.Y., 1982,Table of Content.
- Waltimo, et al, “A novel bite force recorder and maximal isometric bite force values for healthy young adults”, Scandinavian Journal of Dental Research 1993; 101: 171-175.
- Waltimo, et al, “Maximal bite force and its association with signs and symptoms of craniomandibular disorders in young Finnish non-patients”, Acta Odontol Scand 53 (1995): 254-258.
- Waterman et al., “Stabilization of Pharmaceuticals to Oxidative Degradation”, Pharmaceutical Development and Technology, vol. 7(1), pp. 1-32, (2002).
- Waters et al., “Intravenous Quetiapine-Cocaine Use (“Q-Ball”)”, Letter to the Editor, Am. J. Psychiatry, 164(1): pp. 173-174 (2007).
- Weiss, U., “Derivatives of Morphine. I 14-Dihydroxydihydromorphinone,” J. Am. Chem. Soc. 77, pp. 5891-5892, Nov. 20, 1955.
- West, Anthony R., Solid state chemistry and its applications, Wiley, New York, 1988, pp. 358 and 365.
- Wikipedia—Dextromethorphan Aug. 12, 2013 (and attached related English-language entry dated Dec. 11, 2013).
- Woodburn, K.R. et al., Vascular complications of injecting drug misuse, Br. J. of Surgery, vol. 83, 1996, pp. 1329-1334.
- Wu N, et al. Mathematical modeling and in vitro study of controlled drug release via a highly swellable and dissoluble polymer matrix: polyethylene oxide with high molecular weights, J Control Release. Feb. 16, 2005;102(3):569-581.
- Yang et al., “Zero-Order Release Kinetics from a Self-Correcting Floatable Asymmetric Configuration Drug Delivery System”, Journal of Pharmaceutical Sciences, vol. 85, No. 2, Feb. 1996, pp. 170-173.
- Yang, et al; “Characterization of Compressibility and Compactibility of Poly(ethylene oxide) Polymers for Modified Release Application by Compaction Simulator”; Journal of Pharmaceutical Sciences, vol. 85, No. 10, pp. 1085-1090, Oct. 1996.
- Yarbrough et al, Letters to Nature “Extraordinary effects of mortar-and-pestle grinding on microstructure of sintered alumina gel”, Nature 322, pp. 347-349 (Abstract only) (Jul. 24, 1986).
- Yeh et al., Stability of Morphine in Aqueous Solution III: Kinetics of Morphine Degradation in Aqueous Solution, Wiley Subscription Services, Inc., Journal of Pharmaceutical Sciences, 50(1): 35-42 (1961).
- Zeeshan, F and N. Bukhari, “Development and Evaluation of a Novel Modified-Release Pellet-Based Tablet System for the Delivery of Loratadine and Pseudophedrine Hydrochloride as Model Drugs,” AAPS PharmaSciTech 11(2); 910-916 (available on-line May 22, 2010).
- Zhang et al., “Properties of Sustained-Release Tablets Prepared by Hot-Melt Extrusion” Pharmaceutical Development and Technology, 1999, 4(2), 241-250.
- Decision of the United States District Court for the Southern District of New York, in In re Endo Pharmaceuticals Inc. and Grünenthal GmbH v. Amneal Pharmaceuticals, LLC et al., Findings of Fact and Conclusions of Law, District Judge Thomas P. Griesa, New York, New York, Jan. 14, 2015.
- Decision of the United States District Court for the Southern District of New York, in In re Oxycontin Antitrust Litigation, Purdue Pharma LP v. Teva Pharmaceuticals, Findings of Fact and Conclusions of Law, District Judge Sidney H. Stein, New York, New York, Jan. 14, 2014.
- U.S. Court of Appeals, Federal Circuit, Purdue Pharma L.P. v. Epic Pharma, LLC, 117 USPQ2d 1733 (Fed. Cir. 2016).
- Al-Angari, A. et al. “The compaction properties of polyethylene glycols,” J Pharm. Pharmacol. (1985) 37:151-153.
- Al-Nasassrah et al. , “The effect of an increase in chain length on the mechanical properties of polyethylene glycols,” European Journal of Pharmaceutics and Biopharmaceutics 46 (1998) 31-38.
- Anderson, S.L. et al., “A Model for Antiplasticization in Polystyrene,” Macromolecules 28:2944-54 (1995).
- Back, D.M.et al., “Ethylene Oxide Polymers”, in Kirk-Othmer Encyclopedia of Chemical Technology. 2000, John Wiley & Sons, Inc., vol. 10, 673-696.
- Bailey, F.E., et al., “High Molecular Weight Polymers of Ethylene Oxide” Solution Properties Industrial and Engineering Chemistry, 1958. 50(1): 8-11.
- Balogh, E., “Tastes in and Tastes of Paprika,” in Taste: Proceedings of the Oxford Symposium on Food and Cookery 28 (Tom Jaine Ed.) 1988, pp. 25-40.
- Baumann, T., “Pain Management,” Pharmacotherapy: A Pathophysiologic Approach (J.T. DiPiro et al. eds., McGraw-Hill 4th ed. 1999), Ch. 56, 1014-1026.
- Baumrucker, S.J., “OxyContin, the Media, and Law Enforcement”, American Journal of Hospice & Palliative Care, 18:3 (May/Jun. 2001), 154-156.
- Choi, S., et al., “Development of a Directly Compressible Poly(Ethylene Oxide) Matrix for the Sustained-Release of Dihydrocodeine Bitartrate”, Drug Development and Industrial Pharmacy, vol. 29, No. 10, pp. 1045-1052, 2003.
- Choi, S., et al., “Hydrophilic Matrix Formulations of Dihydrocodeine Bitartrate with Polyethylene Oxide by Direct Compression,” Proceedings of the 29th Annual Meeting of the Controlled Release Society, in collaboration with the Korea Society for Biomaterials, Minneapolis, 1st Edition, 2002, 984-985.
- Ciccone, P. E., “Attempted Abuse of Concerta,” Letters to the Editor, J. Am. Acad. Child Adolesc. Psychiatry, 41:7 (Jul. 2002).
- Controversies in ADHD: A Breakfast Symposium—Concerta.
- Crowley, M. et al., Pharmaceutical Applications of Hot-Melt Extrusion: Part I. Drug Dev. & Indus. Pharmacy (2007) 33:909-926.
- Crowley, M. et al., “Properties of Hot-Melt Extruded CPM Tablets Using Hydrophilic Polymers,” poster presentation, (2000).
- Crowley, M., “Physicochemical and Mechanical Characterization of Hot-Melt Extruded Dosage Forms.” Dissertation presented to the Faculty of the Graduate School of The University of Texas at Austin. (May 2003).
- Crowley, M., et al., “Evaluation of a Hot Melt Extrusion Technique using a Hydrophilic Thermal Polymer and Retardant for the Preparation of Extended Release Chlorpheniramine Maleate Tablets,” in American Association of Pharmaceutical Scientists: Indianapolis, IN (2000).
- Crowley0000001-Crowley0000127.
- Davies, N. “Sustained Release and Enteric Coated NSAIDs: Are They Really GI Safe?” J. Pharm. & Pharmaceut. Sci., 2(1):5-14, 1999.
- Declaration of Dr. James W. McGinity, dated Oct. 28, 2009; online, retrieved from: http://www.accessdata.fda.gov/dmgsatfda_docs/labeV2013/021121s032lbl.pdf.
- Dimitrov, M, et al., “Study of Verapamil hydrochloride release from compressed hydrophilic Polyox-Wsr tablets.” Int'l J Pharmaceutics (1999) 189:105-111.
- Dittmer, D.K., et al., “Glue-Sniffing Neuropathies,” Canadian Family Physician 39:1965-1971 (1993).
- Donnelly, C.L., “ADHD Medications: Past and Future,” Behavioral Health Management, May/Jun. 2002, 28 & 30.
- Dow, “Material Safety Data Sheet: POLYOX(TM) WSR 30” (effective date: Sep. 18, 2001).
- Dow, “Polyox Water-Soluble Resins: Degradation of Water-Soluble Resins,” Technical Data (Oct. 2002).
- Drug Bank “Oxymorphone,” 2015; online, available at: www.dmgbank.ca/chugs/db01192 printed Jul. 1, 2015.
- Endo Pharmaceuticals Inc. v. Teva Pharmaceuticals USA, Inc. (S.D.N.Y 2015)—Redacted Version.
- FDA News Release, “FDA approves abuse-deterrent labeling for reformulated OxyContin,” Apr. 16, 2013, available at http://www.fda.gov/NewsEvents/Newsroom/Press.Announcements/ucm348252.htm.
- FDA, “Notice of Determination that OxyContin Drug Products Covered by NDA 20-553 Were Withdrawn From Sale for Reasons of Safety or Effectiveness.” Federal Register, vol. 78, No. 75, Apr. 18, 2013, 23273-23274.
- Final Draft Labeling for Concerta Extended-Release Tablets Attachment to Approval Letter (2000); available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2000/21121lbl.pdf.
- Greenhill, L.L., et al., “Practice Parameter for the Use of Stimulant Medications in the Treatment of Children, Adolescents, and Adults,” J. Am. Acad. Child Adolesc. Psychiatry, 41:2 Supplement, 26S-49S (Feb. 2002).
- Griffith, D., “Potential new ADHD drug creating lots of big hopes,” Sacramento Bee (California), Oct. 30, 2002.
- Huang, H. et al., “Preparation of Controlled Release Oral Dosage Forms by Low Temperature Melt Extrusion,” AAPS PharmSci. 2000 2(S1).
- Jaffe, S.L., “Failed Attempts at Intranasal Abuse of Concerta,” Letters to the Editor, J. Am. Acad. Child Adolesc. Psychiatry, 41:1 (Jan. 2002).
- Jannsen Pharmaceuticals, Inc. Concerta Labeling Revisioins, Dec. 12, 2013; online, retrieved from: http://www.accessdata.fda.gov/dmgsatfda_docs/labeV2013/021121s032lbl.pdf.
- Joint Claim Construction and Prehearing Statement, dated Jul. 11, 2014. Janssen Pharmaceuticals, Inc. and Grünenthal GmbH v. Actavis Elizabeth LLC and Alkem Laboratories Limited, Civil Action No. 2:13-cv-04507 CCC-MF (D.N.J.), Janssen Pharmaceuticals, Inc. and Grünenthal GmbH v. Roxane Laboratories, Inc., Civil Action No. 2:13-cv-06929 CCC-MF (D.N.J.), and Janssen Pharmaceuticals, Inc. and Grünenthal GmbH v. Alkem Laboratories Limited, Civil Action No. 2:13-cv-07803 CCC-MF (D.N.J.).
- Kibbe, Coloring Agents, in Handbook of Pharmaceutical Excipients (3d ed. 2000).
- Kidokoro, M. et al. ,“Properties of Tablets Containing Granulations of Ibuprofen and Acrylic Copolymers Prepared by Thermal Processes,” Pharm Dev. and Tech. , 6:263-275 (2001).
- Kinjo, N. et al, “Antiplasticization in the Slightly Plasticized Poly(vinyl chloride),” Polymer Journal 4(2):143-153 (1973).
- Larhib, H. et al., “Compressing polyethyelene glycols: the effect of compression pressure and speed,” Int 'l J Pharmaceutics (1997) 147: 199-205.
- Lieberman, H., et al., Pharmaceutical Dosage Forms: Tablets, vol. 2, Ch. 5: Granulation Technology and Tablet Characterization (1990), Table of contents and 245-348.
- Lyons et al., “Twitch Interpolation in the Assessment of the Maximum Force-Generating Capacity of the Jaw-Closing Muscles in Man,” Arch. Oral. Biol. 41:12, 1161-1168 (1996).
- Makki, A, et. Al., Eds., A Dictionary of American Idioms, 4th Ed. Barron's, New York (2004), 342-343.
- Markovitz, H., et al. “Calculations of Entanglement Coupling Spacings in Linear Polymers.” Journal of Physical Chemistry, 1962. 66(8): 1567-1568.
- McCrum, N., et al., Principles of Polymer Engineering. 2nd ed., New York: Oxford University Press. 447(1997), Chapter 7, 296-351.
- McGinity, J.W. et al., “Melt-Extruded Controlled-Release Dosage Forms” in Pharmaceutical Extrusion Technology, Ghebre-Sellassie, I. and Martin, C., Eds., Marcel Dekker, Inc., New York, 2003, Chapter 10, 183-208.
- McQuay, H. et a. “Methods of Therapeutic Trials,” Textbook of Pain 1125-1138 (P.D. Wall & R. Melzack eds., Elsevier 4th ed. 1999), Table of Contents and 1125-1138.
- Miura et al., “Comparison of Maximum Bite Force and Dentate Status Between Healthy and Frail Elderly Persons,” J. Oral Rehabilitation, vol. 28 (2001), pp. 592-595.
- Miyagawa, Y. et al., “Controlled-release of diclofenac sodium from wax matrix granulate,” Int 'l J. Pharmaceutics (1996) 138:215-224.
- National Drug Intelligence Center Information Bulletin “OxyContin Diversion and Abuse” Jan. 2001.
- Payne, H. et al., Denatonium Benzoate as a Bitter Aversive Additive in Ethylene Glycol and Methanol-Based Automotive Products, SAE Technical Paper 930589, Abstract (1993).
- Pilpel, N., et al. “The effect of temperature on the tensile strength and disintegration of paracetamol and oxytetracylcine tablets,” J Pharm Pharmac., 29:389-392 (1977).
- Polyox Water-Soluble Resins NF in Pharmaceutical Applications, Dow Chemical Company, Aug. 2002.
- Purdue Pharma LP Material Safety Data Sheet, OxyContin Tablets, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, Version Sep. 10, 2016; available at www.purduephruma.com/msdss/oxycontin_msds.pdf.
- Rauwendaal, Chris, PhD, Responsive Expert Report of Chris Rauwendaal, Ph.D. Regarding Expert Report of Michael M. Crowley, Ph.D., dated Jul. 17, 2015.
- Repka, M. et al. Pharmaceutical Applications of Hot-Melt Extrusion: Part II. Drug Dev. & Indus. Pharmacy (2007) 33:1043-1057.
- Saravanan, M. et al., “The Effect of Tablet Formulation and Hardness on in Vitro Release of Cephalexin from Eudragit L100 Based Extended Release Tablets,” Biol. Pharm. Bull. (2002) 25(4):541-545.
- Seitz, J.A.; et al., “Evaluation of the Physical Properties of Compressed Tablets 1: Tablet Hardness and Friability,” J. of Pharm. Sci. , 54:1353-1357 (1965).
- Shah, et al., “Some Effects of Humidity and Heat on the Tableting Properties of Microcrystalline Cellulose Formulations 1,” J. of Pharm. Sci., 57:181-182 (1967).
- Singhal, et al., Handbook of Indices of Food Quality and Authenticity (1997), “Capsicum” p. 398-299.
- Smith, K.L. et al. “High Molecular Weight Polymers of Ethylene Oxide—Plastic Properties.” Industrial and Engineering Chemistry, 1958. 50(1): 12-16.
- Tapentadol Pre-Review Report, Expert Committee on Drug Dependency Thirty-Fifth Meeting Hammamet, Tunisia, Jun. 4-8, 2012, available at http ://www.who.int/medicines/areas/quality_safety/5.2Tapentadolpre-review.pdf.
- Tiwari, D., et al., “Evaluation of polyoxyethylene homopolymers for buccal bioadhesive drug delivery device formulations.” AAPS Pharmsci, 1999. 1(3): Article 13.
- Wilkins, J.N., “Pharmacotherapy of Schizophrenia Patients with Comorbid Substance Abuse,” Schizophrenia Bulletin, 23:215-228 (1997).
- World Health Org., Cancer Pain Relief With a Guide to Opioid Availability (2d ed. 1996).
- Yin, T.P., et al., “Viscoelastic Properties of Polyethylene Oxide in Rubber-Like State.” Journal of Physical Chemistry, 1961. 65(3): 534-538.
- Zacny, J. et al. Drug & Alcohol Dependence (2003) 69:215-232.
- Zhang, F., “Hot-Melt Extrusion as a Novel Technology to Prepare Sustained-Release Dosage Forms,” Dissertation University of Texas at Austin, Dec. 1999.
- M. Xu et al., “Evaluation of the coat quality of sustained release pellets by individual pellet dissolution methodology,” Int. J. Pharm. 478 (2015) 318-327.
- Schilling, et al., “Novel application of hot-melt extrusion for the preparation of monolithic matrices containing enteric-coated particles.” International Journal of Pharmaceutics 400 (2010) 34-31.
- Fathima, N. et al. “Drug-excipient interaction and its importance in dosage form development,” Journal of Applied Pharmaceutical Science 01 (06); 2011, pp. 66-71.
- Starch 1500, Partially Pregelatinized Maize Starch, technical data from Colorcon, Feb. 2016, 6 pages.
- Remington, Chapter 45, pp. 996-1035.
- COMPAP 90 technical data sheet Mar. 2014; 1 page.
- Dabbagh, et al. “Release of Propranolol Hydrochloride from Matrix Tablets Containing Sodium Carboxymethylcellulose and Hydroxypropylmethylcellulose”; 1999; Pharmaceutical Development and Technology, 4(3), 313-324.
- Extended European Search Report for Application No. EP 16182124.4-1455, dated Jan. 17, 2017.
- Furu et al. “Use of ADHD drugs in the Nordic countries: a population-based comparison study,” Acta Psychiatrica Scandinavia, May 2010.
- PCT International Search Report and Written Opinion for PCT Application No. PCT/EP2017/070396 dated Sep. 8, 2017.
- Turkington, R., “Amphetamines,” in Chemicals used for Illegal Purposes. A Guide for first Responders to Identify Explosives, Recreational Drugs, and Poisons, 2010, p. 247.
- Houston, T.E., et al., “Bite Force and Bite Pressure: Comparison of Humans and Dogs,” http://www.glapbta.com/BFBP.pdf, 2003, pp. 1-7.
- Sigma-Aldrich entry for CAS No. 9010-88-2; www.sigmaaldrich.com/catalog/product/aldrich/182249?lang=en®ion=US (downloaded Jun. 2018).
- U.S. Appl. No. 60/287,509, filed Dec. 2, 2002, Joshi et al.
- U.S. Appl. No. 60/288,211, filed Sep. 2, 2004, Oshlack et al.
- U.S. Appl. No. 60/310,514, filed Apr. 3, 2003, Oshlack et al.
- U.S. Appl. No. 60/310,534, filed Apr. 10, 2003, Wright et al.
- U.S. Appl. No. 60/376,470, filed Jan. 15, 2004, Ayer et al.
- U.S. Appl. No. 60/384,442, filed Dec. 4, 2003, Fink et al.
- King, Remington's Pharmaceutical Sciences 17th ed., Chapter 78, p. 1418-1419 (1985).
- Sumitomo Seika Chemicals, Co., Ltd, “Certificate of Analysis,” Product: Polyethylene Oxide; Grade: PEO-18NF; Feb. 2, 2016.
- Sumitomo Seika Chemicals, Co., Ltd, “Certificate of Analysis,” Product: Polyethylene Oxide; Grade: PEO-20NF; May 15, 2013.
- Sumitomo Seika Chemicals, Co., Ltd, “Certificate of Analysis,” Product: Polyethylene Oxide; Grade: PEO-20NF; Jan. 23, 2012.
- Sumitomo Seika Chemicals, Co., Ltd, “Certificate of Analysis,” Product: Polyethylene Oxide; Grade: PEO-20NF; Feb. 3, 2016.
- Pharma Tips ([online] retrieved on Mar. 22, 2018 from http://ww.pharmatips.in/Articles/Pharmaceutics/Tablet/Co-Processed-Directly-Compressed-Adjutants.aspx May 2011: 10 pages).
- De Brabander C., et al., “Development and evaluation of sustained release mini-matrices prepared via hot melt extrusion,” Journal of Controlled Release 89 (2003), 235-247.
- Goodman and Gilman, 1985, 7th edition, chapter 29, 674-715.
- Quadros, E. et al., “Evaluation of a novel colonic delivery device in vivo,” STP Pharma Sci. 5, 77-82 (1995).
- Wooten, Marvin R. et al., Intracerebral Hemorrhage and Vasculitis Related to Ephedrine Abuse, 13 Annals of Neurology 337 (1983).
- Theeuwes, Felix et al., Osmotic Systems for Colon-Targeted Drug Delivery in Colonic Drug Absorption and Metabolism (Peter R. Bieck ed., 1993).
- European Pharmacopoeia 3.0, 2.9.8 “Resistance to Crushing of Tablets”, 1997, p. 135.
- Nickerson, B., Sample Preparation of Pharmaceutical Dosage Forms, Springer, New York (2011); Chapter 1, pp. 3-48.
- Polyox Water-Soluble Resins in Pharmaceutical Applications. Dow Chemicals. Published 2004.
- Bannwarth, Bernard, “Will Abuse-Deterrent Formulations of Opioid Analgesics be Successful in Achieving Their Purpose?”, Drugs, 2012, vol. 72, pp. 1713-1723.
- PCT International Search Report and Written Opinion for PCT Application No. PCT/EP2016/052046 dated Apr. 12, 2016.
Type: Grant
Filed: Sep 14, 2016
Date of Patent: Nov 20, 2018
Patent Publication Number: 20170000739
Assignee: GRÜNENTHAL GMBH (Aachen)
Inventors: Johannes Bartholomäus (Aachen), Heinrich Kugelmann (Aachen), Elisabeth Arkenau-Marić (Köln)
Primary Examiner: Michael G Hartley
Assistant Examiner: Melissa J Perreira
Application Number: 15/265,263
International Classification: A61K 9/20 (20060101); A61K 31/135 (20060101); A61K 31/485 (20060101); A61K 31/515 (20060101); A61K 31/5513 (20060101); A61K 47/10 (20170101); A61K 9/00 (20060101);